Novel 14 and 15 membrered ring compounds

ABSTRACT

The present invention relates to 14- or 15-membered macrolides substituted at the 4″ position of formula (I)  
                 
and pharmaceutically acceptable derivatives thereof, to processes for their preparation and their use in therapy or prophylaxis of systemic or topical microbial infections in a human or animal body.

The present invention relates to novel semi-synthetic macrolides havingantimicrobial activity, in particular antibacterial activity. Moreparticularly, the invention relates to 14- and 15-membered macrolidessubstituted at the 4″ position, to processes for their preparation, tocompositions containing them and to their use in medicine.

Macrolide antibacterial agents are known to be useful in the treatmentor prevention of bacterial infections. However, the emergence ofmacrolide-resistant bacterial strains has resulted in the need todevelop new macrolide compounds. For example, EP 0 895 999 describesderivatives modified at the 4″ position of the macrolide ring havingantibacterial activity.

According to the present invention, we have now found novel 14- and15-membered macrolides substituted at the 4″ position which also haveantimicrobial activity.

Thus, the present invention provides compounds of general formula (I)

wherein

A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—,—N(R⁷)—CH₂—, —CH₂—N(R⁷)—, —CH(NR⁸R⁹)— and —C(═NR¹⁰)—;

R¹ is —O(CH₂)_(d)XR¹¹;

R² is hydrogen or a hydroxyl protecting group;

R³ is hydrogen, C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to10 membered fused bicyclic heteroaryl;

R⁴ is hydroxy, C₃₋₆alkenyloxy optionally substituted by 9 to 10 memberedfused bicyclic heteroaryl, or C₁₋₆alkoxy optionally substituted byC₁₋₆alkoxy or —O(CH₂)_(e)NR⁷R¹²,

R⁵ is hydroxy, or

R⁴ and R⁵ taken together with the intervening atoms form a cyclic grouphaving the following structure:

wherein Y is a bivalent radical selected from —CH₂—, —CH(CN)—, —O—,—N(R¹³)— and —CH(SR¹³)—;

R⁶ is hydrogen or fluorine;

R⁷ is hydrogen or C₁₋₆alkyl;

R⁸ and R⁹ are each independently hydrogen, C₁₋₆alkyl, —C(═NR¹⁰)NR¹⁴R¹⁵or —C(O)R¹⁴, or

R⁸ and R⁹ together form ═CH(CR¹⁴R¹⁵)_(f)aryl,═CH(CR¹⁴R¹⁵)_(f)heterocyclyl, ═CR¹⁴R¹⁵ or ═C(R¹⁴)C(O)OR¹⁴, wherein thealkyl, aryl and heterocyclyl groups are optionally substituted by up tothree groups independently selected from R¹⁶;

R¹⁰ is —OR¹⁷, C₁₋₆alkyl, —(CH₂)_(g)aryl, —(CH₂)_(g)heterocyclyl or—(CH₂)_(h)O(CH₂)_(i)OR⁷, wherein each R¹⁰ group is optionallysubstituted by up to three groups independently selected from R¹⁶;

R¹¹ is a heterocyclic group having the following structure:

R¹² is hydrogen or C₁₋₆alkyl;

R¹³ is hydrogen or C₁₋₄alkyl optionally substituted by a group selectedfrom optionally substituted phenyl, optionally substituted 5 or 6membered heteroaryl and optionally substituted 9 to 10 membered fusedbicyclic heteroaryl;

R¹⁴ and R¹⁵ are each independently hydrogen or C₁₋₆alkyl;

R¹⁶ is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R²¹,—C(O)OR²¹, —OC(O)R²¹, —OC(O)OR²¹, —NR²²C(O)R²³, —C(O)NR²²R²³, —NR²²R²³,hydroxy, C₁₋₆alkyl, —S(O)_(k)C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(m)aryl or—(CH₂)_(m)heteroaryl, wherein the alkoxy group is optionally substitutedby up to three groups independently selected from —NR¹⁴R¹⁵, halogen and—OR¹⁴, and the aryl and heteroaryl groups are optionally substituted byup to five groups independently selected from halogen, cyano, nitro,trifluoromethyl, azido, —C(O)R²⁴, —C(O)OR²⁴, —OC(O)OR²⁴, —NR²⁵C(O)R²⁶,—C(O)NR²⁵R²⁶, —NR²⁵R²⁶, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy;

R¹⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₆alkenyl or a 5 or 6membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl andheterocyclic groups are optionally substituted by up to threesubstituents independently selected from optionally substituted 5 or 6membered heterocyclic group, optionally substituted 5 or 6 memberedheteroaryl, —OR²⁷, —S(O)_(n)R²⁷, —NR²⁷R²⁸, —CONR²⁷R²⁸, halogen andcyano;

R¹⁸ is hydrogen, —C(O)OR²⁹, —C(O)NHR²⁹, —C(O)CH₂NO₂ or —C(O)CH₂SO₂R⁷;

R¹⁹ is hydrogen, C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy, C₃₋₇cycloalkyl, or optionally substituted phenyl or benzyl;

R²⁰ is halogen, C₁₋₄alkyl, C₁₋₄thioalkyl, C₁₋₄alkoxy, —NH₂,—NH(C₁₋₄alkyl) or —N(C₁₋₄alkyl)₂;

R²¹ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(p)aryl or —(CH₂)_(p)heteroaryl;

R²² and R²³ are each independently hydrogen, —OR¹⁴, C₁₋₆alkyl,—(CH₂)_(q)aryl or —(CH₂)_(q)heterocyclyl;

R²⁴ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(r)aryl or —(CH₂)_(r)heteroaryl;

R²⁵ and R²⁶ are each independently hydrogen, —OR¹⁴, C₁₋₆alkyl,—(CH₂)_(s)aryl or —(CH₂)_(s)heterocyclyl;

R²⁷ and R²⁸ are each independently hydrogen, C₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl;

R²⁹ is hydrogen,

-   -   C₁₋₆alkyl optionally substituted by up to three groups        independently selected from halogen, cyano, C₁₋₄alkoxy        optionally substituted by phenyl or C₁₋₄alkoxy, —C(O)C₁₋₆alkyl,        —C(O)OC₁₋₆alkyl, —OC(O)C₁₋₆alkyl, —OC(O)C₁₋₆alkyl, —C(O)NR³²R³³,        —NR³²R³³ and phenyl optionally substituted by nitro or        —C(O)OC₁₋₆alkyl,    -   —(CH₂)_(w)C₃₋₇cycloalkyl,    -   —(CH₂)_(w)heterocyclyl,    -   —(CH₂)_(w)heteroaryl,    -   —(CH₂)_(w)aryl,    -   C₃₋₆alkenyl, or    -   C₃₋₆alkynyl;

R³⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, optionally substitutedphenyl or benzyl, acetyl or benzoyl;

R³¹ is hydrogen or R²⁰, or R³¹ and R¹⁹ are linked to form the bivalentradical —O(CH₂)₂— or —(CH₂)_(t)—;

R³² and R³³ are each independently hydrogen or C₁₋₆alkyl optionallysubstituted by phenyl or —C(O)OC₁₋₆alkyl, or

R³² and R³³, together with the nitrogen atom to which they are bound,form a 5 or 6 membered heterocyclic group optionally containing oneadditional heteroatom selected from oxygen, nitrogen and sulfur;

X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a group selected from:

U and B are independently a divalent radical selected from —N(R³⁰)—,—O—, —S(O)_(z)—, —N(R³⁰)C(O)—, —C(O)N(R³⁰)— and —N[C(O)R³⁰]—;

W is —C(R³¹)— or a nitrogen atom;

d is an integer from 2 to 6;

e is an integer from 2 to 4;

f, g, h, m, p, q, r, s and w are each independently integers from 0 to4;

i is an integer from 1 to 6;

j, k, n and z are each independently integers from 0 to 2;

t is 2 or 3;

v is an integer from 1 to 8;

and pharmaceutically acceptable derivatives thereof.

According to another embodiment the present invention provides compoundsof general formula (IA):

wherein

A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—,—N(R⁷)—CH₂—, —CH₂—N(R⁷)—, —CH(NR⁸R⁹)— and —C(═NR¹⁰)—;

R¹ is —O(CH₂)_(d)XR¹¹;

R² is hydrogen or a hydroxyl protecting group;

R³ is hydrogen, C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to10 membered fused bicyclic heteroaryl;

R⁴ is hydroxy, C₃₋₆alkenyloxy optionally substituted by 9 to 10 memberedfused bicyclic heteroaryl, or C₁₋₆alkoxy optionally substituted byC₁₋₆alkoxy or —O(CH₂)_(e)NR⁷R¹²,

R⁵ is hydroxy, or

R⁴ and R⁵ taken together with the intervening atoms form a cyclic grouphaving the following structure:

wherein Y is a bivalent radical selected from —CH₂—, —CH(CN)—, —O—,—N(R¹³)— and —CH(SR¹³)—;

R⁶ is hydrogen or fluorine;

R⁷ is hydrogen or C₁₋₆alkyl;

R⁸ and R⁹ are each independently hydrogen, C₁₋₆alkyl, —C(═NR¹⁰)NR¹⁴R¹⁵or —C(O)R¹⁴, or

R⁸ and R⁹ together form ═CH(CR¹⁴R¹⁵)_(f)aryl,═CH(CR¹⁴R¹⁵)_(f)heterocyclyl, ═CR¹⁴R¹⁵ or ═C(R¹⁴)C(O)OR¹⁴, wherein thealkyl, aryl and heterocyclyl groups are optionally substituted by up tothree groups independently selected from R¹⁶;

R¹⁰ is —OR¹⁷, C₁₋₆alkyl, —(CH₂)_(g)aryl, —(CH₂)_(g)heterocyclyl or—(CH₂)_(h)O(CH₂)_(i)OR⁷, wherein each R¹⁰ group is optionallysubstituted by up to three groups independently selected from R¹⁶;

R¹¹ is a heterocyclic group having the following structure:

R¹² is hydrogen or C₁₋₆alkyl;

R¹³ is hydrogen or C₁₋₄alkyl substituted by a group selected fromoptionally substituted phenyl, optionally substituted 5 or 6 memberedheteroaryl and optionally substituted 9 to 10 membered fused bicyclicheteroaryl;

R¹⁴ and R¹⁵ are each independently hydrogen or C₁₋₆alkyl;

R¹⁶ is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R²¹,—C(O)OR²¹, —OC(O)R²¹, —OC(O)OR²¹, —NR²²C(O)R²³, —C(O)NR²²R²³, —NR²²R²³,hydroxy, C₁₋₆alkyl, —S(O)_(k)C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(m)aryl or—(CH₂)_(m)heteroaryl, wherein the alkoxy group is optionally substitutedby up to three groups independently selected from —NR¹⁴R¹⁵, halogen and—OR¹⁴, and the aryl and heteroaryl groups are optionally substituted byup to five groups independently selected from halogen, cyano, nitro,trifluoromethyl, azido, —C(O)R²⁴, —C(O)OR²⁴, —OC(O)OR²⁴, —NR²⁵C(O)R²⁶,—C(O)NR²⁵R²⁶, —NR²⁵R²⁶, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy;

R¹⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₆alkenyl or a 5 or 6membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl andheterocyclic groups are optionally substituted by up to threesubstituents independently selected from optionally substituted 5 or 6membered heterocyclic group, optionally substituted 5 or 6 memberedheteroaryl, —OR²⁷, —S(O)_(n)R²⁷, —NR²⁷R²⁸, —CONR²⁷R²⁸, halogen andcyano;

R¹⁸ is hydrogen, —C(O)OR²⁹, —C(O)NHR²⁹ or —C(O)CH₂NO₂;

R¹⁹ is hydrogen, C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy, C₃₋₇cycloalkyl, or optionally substituted phenyl or benzyl;

R²⁰ is halogen, C₁₋₄alkyl, C₁₋₄thioalkyl, C₁₋₄alkoxy, —NH₂,—NH(C₁₋₄alkyl) or —N(C₁₋₄alkyl)₂;

R²¹ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(p)aryl or —(CH₂)_(p)heteroaryl;

R²² and R²³ are each independently hydrogen, —OR¹⁴, C₁₋₆alkyl,—(CH₂)_(q)aryl or —(CH₂)_(q)heterocyclyl;

R²⁴ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(r)aryl or —(CH₂)_(r)heteroaryl;

R²⁵ and R²⁶ are each independently hydrogen, —OR¹⁴, C₁₋₆alkyl,—(CH₂)_(s)aryl or —(CH₂)_(s)heterocyclyl;

R²⁷ and R²⁸ are each independently hydrogen, C₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl;

R²⁹ is hydrogen or C₁₋₆alkyl optionally substituted by up to threegroups independently selected from halogen, C₁₋₄alkoxy, —OC(O)C₁₋₆alkyland —OC(O)OC₁₋₆alkyl;

R³⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, optionally substitutedphenyl or benzyl, acetyl or benzoyl;

R³¹ is hydrogen or R²⁰, or R³¹ and R¹⁹ are linked to form the bivalentradical —O(CH₂)₂— or —(CH₂)_(t)—;

X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a group selected from:

U and B are independently a divalent radical selected from —N(R³⁰)—,—O—, —S(O)_(z)—, —N(R³⁰)C(O)—, —C(O)N(R³⁰)— and —N[C(O)R³⁰]—;

W is —C(R³¹)— or a nitrogen atom;

d is an integer from 2 to 6;

e is an integer from 2 to 4;

f, g, h, m, p, q, r and s are each independently integers from 0 to 4;

i is an integer from 1 to 6;

j, k, n and z are each independently integers from 0 to 2;

t is 2 or 3;

v is an integer from 2 to 8;

and pharmaceutically acceptable derivatives thereof.

The term “pharmaceutically acceptable” as used herein means a compoundwhich is suitable for pharmaceutical use. Salts and solvates ofcompounds of the invention which are suitable for use in medicine arethose wherein the counterion or associated solvent is pharmaceuticallyacceptable. However, salts and solvates having non-pharmaceuticallyacceptable counterions or associated solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of the invention and theirpharmaceutically acceptable salts and solvates.

The term “pharmaceutically acceptable derivative” as used herein meansany pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. Preferred pharmaceuticallyacceptable derivatives are salts, solvates, esters, carbamates andphosphate esters. Particularly preferred pharmaceutically acceptablederivatives are salts, solvates and esters. Most preferredpharmaceutically acceptable derivatives are salts and esters, inparticular salts.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent. For example, an aqueous solution of an acidsuch as hydrochloric acid may be added to an aqueous suspension of acompound of formula (I) and the resulting mixture evaporated to dryness(lyophilized) to obtain the acid addition salt as a solid.Alternatively, a compound of formula (I) may be dissolved in a suitablesolvent, for example an alcohol such as isopropanol, and the acid may beadded in the same solvent or another suitable solvent. The resultingacid addition salt may then be precipitated directly, or by addition ofa less polar solvent such as diisopropyl ether or hexane, and isolatedby filtration.

Suitable addition salts are formed from inorganic or organic acids whichform non-toxic salts and examples are hydrochloride, hydrobromide,hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, trifluoroacetate, maleate, malate, fumarate,lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate,oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl oraryl sulphonates (eg methanesulphonate, ethanesulphonate,benzenesulphonate or p-toluenesulphonate) and isethionate.Representative examples include trifluoroacetate and formate salts, forexample the bis or tris trifluoroacetate salts and the mono or diformatesalts.

Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium and salts with organicbases, including salts of primary, secondary and tertiary amines, suchas isopropylamine, diethylamine, ethanolamine, trimethylamine,dicyclohexyl amine and N-methyl-D-glucamine.

Compounds of the invention may have both a basic and an acidic centremay therefore be in the form of zwitterions.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The salts of the compound of formula(I) may form solvates (e.g. hydrates) and the invention also includesall such solvates.

The term “prodrug” as used herein means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, “Prodrugs as Novel DeliverySystems”, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed.,“Bioreversible Carriers in Drug Design”, American PharmaceuticalAssociation and Pergamon Press, 1987, and in D. Fleisher, S. Ramon andH. Barbra “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound ofstructure (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own rightand/or be hydrolyzable under in vivo conditions in the human body.Suitable pharmaceutically acceptable in vivo hydrolysable ester groupsinclude those which break down readily in the human body to leave theparent acid or its salt.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptablederivatives.

With regard to stereoisomers, the compounds of structure (I) have morethan one asymmetric carbon atom. In the general formula (I) as drawn,the solid wedge shaped bond indicates that the bond is above the planeof the paper. The broken bond indicates that the bond is below the planeof the paper.

It will be appreciated that the substituents on the macrolide may alsohave one or more asymmetric carbon atoms. Thus, the compounds ofstructure (I) may occur as individual enantiomers or diastereomers. Allsuch isomeric forms are included within the present invention, includingmixtures thereof.

Where a compound of the invention contains an alkenyl group, cis (Z) andtrans (E) isomerism may also occur. The present invention includes theindividual stereoisomers of the compound of the invention and, whereappropriate, the individual tautomeric forms thereof, together withmixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achievedby conventional techniques, e.g. by fractional crystallization,chromatography or H.P.L.C. A stereoisomeric mixture of the agent mayalso be prepared from a corresponding optically pure intermediate or byresolution, such as H.P.L.C., of the corresponding mixture using asuitable chiral support or by fractional crystallization of thediastereoisomeric salts formed by reaction of the corresponding mixturewith a suitable optically active acid or base, as appropriate.

The compounds of structure (I) may be in crystalline or amorphous form.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

Compounds wherein R² represents a hydroxyl protecting group are ingeneral intermediates for the preparation of other compounds of formula(I).

When the group OR² is a protected hydroxyl group this is conveniently anether or an acyloxy group. Examples of particularly suitable ethergroups include those in which R² is a trialkylsilyl (i.e.trimethylsilyl). When the group OR² represents an acyloxy group, thenexamples of suitable groups R² include acetyl or benzoyl.

R⁶ is hydrogen or fluorine. However, it will be appreciated that when Ais —C(O)NH— or —CH₂—N(R⁷)—, R⁶ is hydrogen.

When R¹¹ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 5, 6, 7 or 8 position to the X groupas above defined. In one embodiment, the heterocyclic is linked in the 6or 7 position. In another embodiment, the heterocyclic is linked in the5 or 8 position. When present, the R²⁰ group or groups may be attachedat any position on the ring. In one embodiment, an R²⁰ group is attachedat the 6 or 7 position.

When R¹¹ is a heterocyclic group having the following structure:

wherein W is —C(R³¹)— where R³¹ is R²⁰ or R³¹ and R¹⁹ are linked to formthe bivalent radical —O(CH₂)₂— or —(CH₂)_(t)—, said heterocyclic islinked in the (i), (ii) or (iii) position to the X group as abovedefined. In one embodiment, the heterocyclic is linked in the (i)position. In another embodiment, the heterocyclic is linked in the (ii)or (iii) position.

When R¹¹ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 5, 6 or 7 position to the X group asdefined above. In one embodiment, the heterocyclic is linked in the 6 or7 position. In another embodiment, the heterocyclic is linked in the 5position. The R²⁰ group or groups may be attached at any position on thering. In one embodiment, an R²⁰ group is attached at the 6 position.

When R¹¹ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 6, 7, 8 or 9 position to the X groupas above defined. In one embodiment, the heterocyclic is linked in the 7or 8 position. In another embodiment, the heterocyclic is linked in the6 or 9 position.

When R¹¹ is a heterocyclic group having the following structure:

wherein W is —C(R³¹)— where R³¹ is R²⁰ or R³¹ and R¹⁹ are linked to formthe bivalent radical —O(CH₂)₂— or —(CH₂)_(t)—, said heterocyclic islinked in the (i), (ii) or (iii) position to the X group as abovedefined. In one embodiment, the heterocyclic is linked in the (i)position. In another embodiment, the heterocyclic is linked in the (ii)or (iii) position.

When R¹¹ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 2, 3 or 4 position to the X group asabove defined. In one embodiment, the heterocyclic is linked in the 2 or3 position. In another embodiment, the heterocyclic is linked in the 4position.

The term “alkyl” as used herein as a group or a part of a group refersto a straight or branched hydrocarbon chain containing the specifiednumber of carbon atoms. For example, C₁₋₁₀alkyl means a straight orbranched alkyl containing at least 1, and at most 10, carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl,t-butyl, hexyl, heptyl, octyl, nonyl and decyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or t-butyl.

The term “C₃₋₇cycloalkyl” group as used herein refers to a non-aromaticmonocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “alkoxy” as used herein refers to a straight or branched chainalkoxy group containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy and hexyloxy. A C₁₋₄alkoxy group is preferred, for examplemethoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or2-methylprop-2-oxy.

The term “alkenyl” as used herein as a group or a part of a group refersto a straight or branched hydrocarbon chain containing the specifiednumber of carbon atoms and containing at least one double bond. Forexample, the term “C₂₋₆alkenyl” means a straight or branched alkenylcontaining at least 2, and at most 6, carbon atoms and containing atleast one double bond. Similarly, the term “C₃₋₆alkenyl” means astraight or branched alkenyl containing at least 3, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to, ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and1,1-dimethylbut-2-enyl. It will be appreciated that in groups of theform —O—C₂₋₆alkenyl, the double bond is preferably not adjacent to theoxygen.

The term “alkynyl” as used herein as a group or a part of a group refersto a straight or branched hydrocarbon chain containing the specifiednumber of carbon atoms and containing at least one triple bond. Forexample, the term “C₃₋₆alkenyl” means a straight or branched alkynylcontaining at least 3, and at most 6, carbon atoms containing at leastone triple bond. Examples of “alkynyl” as used herein include, but arenot limited to, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and3-methyl-1-butynyl.

The term “aryl” as used herein refers to an aromatic carbocyclic moietysuch as phenyl, biphenyl or naphthyl.

The term “heteroaryl” as used herein, unless otherwise defined, refersto an aromatic heterocycle of 5 to 10 members, having at least oneheteroatom selected from nitrogen, oxygen and sulfur, and containing atleast 1 carbon atom, including both mono and bicyclic ring systems.Examples of heteroaryl rings include, but are not limited to, furanyl,thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl,1,3-benzodioxazolyl, indolyl, benzothiazolyl, furylpyridine,oxazolopyridyl and benzothiophenyl.

The term “5 or 6 membered heteroaryl” as used herein as a group or apart of a group refers to a monocyclic 5 or 6 membered aromaticheterocycle containing at least one heteroatom independently selectedfrom oxygen, nitrogen and sulfur. Examples include, but are not limitedto, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazinyl.

The term “9 to 10 membered fused bicyclic heteroaryl” as used herein asa group or a part of a group refers to quinolinyl, isoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl,benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl,benzothiazolyl, furylpyridine, oxazolopyridyl or benzothiophenyl.

The term “heterocyclyl” as used herein, unless otherwise defined, refersto a monocyclic or bicyclic three- to ten-membered saturated ornon-aromatic, unsaturated hydrocarbon ring containing at least oneheteroatom selected from oxygen, nitrogen and sulfur. Preferably, theheterocyclyl ring has five or six ring atoms. Examples of heterocyclylgroups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl,piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

The term “5 or 6 membered heterocyclic group” as used herein as a groupor part of a group refers to a monocyclic 5 or 6 membered saturatedhydrocarbon ring containing at least one heteroatom independentlyselected from oxygen, nitrogen and sulfur. Examples of such heterocyclylgroups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl,piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

The term “halogen” refers to a fluorine, chlorine, bromine or iodineatom.

The terms “optionally substituted phenyl”, “optionally substitutedphenyl or benzyl”, “optionally substituted 5 or 6 membered heteroaryl”,“optionally substituted 9 to 10 membered fused bicyclic heteroaryl” or“optionally substituted 5 or 6 membered heterocyclic group” as usedherein refer to a group which is substituted by 1 to 3 groups selectedfrom halogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy, nitro, cyano, amino,C₁₋₄alkylamino or diC₁₋₄alkylamino, phenyl and 5 or 6 memberedheteroaryl.

In one embodiment, A is —C(O)—, —C(O)NH—, —NHC(O)—, —N(R⁷)—CH₂—,—CH₂—N(R⁷)— or —CH(NR⁸R⁹)—. In another embodiment, A is —C(O)—,—C(O)NH—, —NHC(O)—, —CH₂—N(R⁷)—, —CH(NR⁸R⁹)— or —C(═NR¹⁰—. In a furtherembodiment, A is —C(O)—, —C(O)NH—, —NHC(O)—, —CH₂—NR⁷— or —CH(NR⁸R⁹)—.Representative examples of A include —C(O)— and —N(R⁷)—CH₂—. Inparticular, A is —C(O)—.

A representative example of R² is hydrogen.

Representative examples of R³ include hydrogen and C₁₋₄alkyl, forexample hydrogen and methyl. In particular, R³ is methyl.

In one embodiment, R⁴ and R⁵ are hydroxy. Alternatively, R⁴ and R⁵ takentogether with the intervening atoms form a cyclic group having thefollowing structure:

wherein Y is a bivalent radical selected from —O— and —N(R¹³)—.

A representative example of R⁶ is hydrogen.

A representative example of R⁷ is C₁₋₆alkyl, for example C₁₋₄alkyl, inparticular methyl.

In one embodiment, R¹¹ includes heterocyclic groups having the followingstructures:

wherein the heterocyclic is linked in the 6 or 7 position to the X groupas above defined; heterocyclic groups having the following structure:

wherein W is —C(R³¹)— and R³¹ and R¹⁹ are linked to form the bivalentradical —(CH₂)_(t)—, and the heterocylic is linked in the (ii) or (iii),position to the X group as above defined; and heterocyclic groups havingthe following structure:

the heterocyclic is linked in the 7 or 8 position to the X group asabove defined.

Representative examples of R¹¹ include heterocyclic groups having thefollowing structures:

wherein the heterocyclic is linked in the 6 or 7 position to the X groupas above defined, and heterocyclic groups having the followingstructure:

wherein W is —C(R³¹)— and R³¹ and R¹⁹ are linked to form the bivalentradical —(CH₂)_(t)—, and the heterocylic is linked in the (ii) or (iii),position to the X group as above defined.

A further representative example of R¹¹ is a heterocyclic group havingthe following structure:

said heterocyclic is linked in the 7 or 8 position to the X group asabove defined.

In one embodiment, R¹³ is hydrogen or C₁₋₄alkyl substituted by a groupselected from optionally substituted phenyl, optionally substituted 5 or6 membered heteroaryl and optionally substituted 9 to 10 membered fusedbicyclic heteroaryl. Representative examples of R¹³ include hydrogen andC₁₋₄alkyl, for example hydrogen and methyl.

In one embodiment, R¹⁸ is hydrogen, —C(O)OR²⁹, —C(O)NHR²⁹ or—C(O)CH₂NO₂. In a further embodiment, R¹⁸ is —C(O)OR²⁹, —C(O)NHR²⁹ or—C(O)CH₂NO₂. A representative example of R¹⁸ is —C(O)OR²⁹, wherein R²⁹is hydrogen.

Representative examples of R¹⁹ include C₁₋₄alkyl, in particular ethyl,and C₃₋₇cycloalkyl, in particular cyclopropyl.

In one embodiment, R²⁰ is halogen or C₁₋₄alkyl. Representative examplesof R²⁰ include halogen, in particular chlorine or fluorine. Furtherrepresentative examples of R²⁰ include C₁₋₄alkyl, in particular methyl.

In one embodiment, R²⁹ is hydrogen or C₁₋₆alkyl optionally substitutedby up to three groups independently selected from halogen, C₁₋₄alkoxy,—OC(O)C₁₋₆alkyl and —OC(O)OC₁₋₆alkyl. A representative example of R₂₉ ishydrogen.

Representative examples of R³⁰ include hydrogen and C₁₋₄alkyl, inparticular hydrogen and methyl.

A representative example of R³¹ is hydrogen, or R³¹ and R¹⁹ are linkedto form the divalent radical —(CH₂)_(t)—.

In one embodiment, X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a group selectedfrom:

In another embodiment, X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a groupselected from:

Representative examples of X are —U(CH₂)_(v)B— and —U(CH₂)_(v)—.

Further representative examples of X are

In one embodiment, U and B are independently a divalent radical selectedfrom —N(R³⁰)—, —O—, —S(O)_(z)— and —C(O)N(R³⁰)—. Representative examplesof U and B include the divalent radicals —N(R³⁰)—, —O— and —S(O)_(z)—. Afurther representative example of U and B is —C(O)N(R³⁰)—.

In one embodiment, when X is —U(CH₂)_(v)B—, U is selected from thedivalent radicals —N(R³⁰)—, and —C(O)N(R³⁰)— and B is selected from thedivalent radicals —N(R³⁰)—, —O— and —S(O)_(z)—. In particular, U is—N(R³⁰)— and B is selected from the divalent radicals —N(R³⁰)—, —O— and—S(O)_(z)—. For example, U is —N(R³⁰)— and B is selected from thedivalent radicals —N(R³⁰)— and —S(O)_(z)—.

In one embodiment, when X is —U(CH₂)_(v)—, U is selected from thedivalent radicals —N(R³⁰)— and —O—. For example, U is —N(R³⁰)—.

Representative examples of Y include the bivalent radicals —O— and—N(R¹³)—.

Representative examples of d include 2 and 3.

A representative example of t is 3.

In one embodiment, v is an integer of from 2 to 8. A representativeexample of v is 2 to 4, in particular 2 or 3.

A representative example of z is 0.

Representative examples of j include 0 and 1.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.It is also to be understood that the present invention encompassescompounds of formula (I) in which a particular group or parameter, forexample R⁷, R¹⁴, R¹⁵, R¹⁶, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,R³⁰, R³², R³³, k, m, n, p, q, r, s and z may occur more than once. Insuch compounds it will be appreciated that each group or parameter isindependently selected from the values listed.

Particularly preferred compounds of the invention are:

4″-O-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-erythromycinA 11,12-carbonate;

4″-O-(3-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]-methylamino}propyl)-6-O-methyl-erythromycinA 11,12-carbonate;

4′-O-{3-[2-(2-carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate;

4″-O-(3-{[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate;

4″-O-(3-{[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}propyl)-6-O-methyl-erythromycinA 11,12-carbonate;

and pharmaceutically acceptable derivatives thereof.

Further particularly preferred compounds of the invention are:

4″-O-{2-[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-ethyl}-6-O-methyl-erythromycinA;

4″-O-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate;

4″-O-{3-[[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate;

4″-O-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylcarbamoyl]-propyl}-azithromycin;

4″-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin11,12-cyclic carbonate;

4″-O-{2-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylamino]-ethyl}-azithromycin;

4-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin;

and pharmaceutically acceptable derivatives thereof.

Compounds according to the invention also exhibit a broad spectrum ofantimicrobial activity, in particular antibacterial activity, against awide range of clinical pathogenic microorganisms. Using a standardmicrotiter broth serial dilution test, compounds of the invention havebeen found to exhibit useful levels of activity against a wide range ofpathogenic microorganisms. In particular, the compounds of the inventionmay be active against strains of Staphylococcus aureus, Streptopococcuspneumoniae, Moraxella catarrhalis, Streptococcus pyogenes, Haemophilusinfluenzae, Enterococcus faecalis, Chlamydia pneumoniae, Mycoplasmapneumoniae and Legionella pneumophila. The compounds of the inventionmay also be active against resistant strains, for example erythromycinresistant strains. In particular, the compounds of the invention may beactive against erythromycin resistant strains of Streptococcuspneumoniae, Streptococcus pyogenes and Staphylococcus aureus.

The compounds of the invention may therefore be used for treating avariety of diseases caused by pathogenic microorganisms, in particularbacteria, in human beings and animals. It will be appreciated thatreference to treatment includes acute treatment or prophylaxis as wellas the alleviation of established symptoms.

Thus, according to another aspect of the present invention we provide acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in therapy.

According to a further aspect of the invention we provide a compound offormula (I) or a pharmaceutically acceptable derivative thereof for usein the therapy or prophylaxis of systemic or topical microbialinfections in a human or animal subject.

According to a further aspect of the invention we provide the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof in the manufacture of a medicament for use in the treatment orprophylaxis of systemic or topical microbial infections in a human oranimal body.

According to a yet further aspect of the invention we provide a methodof treatment of the human or non-human animal body to combat microbialinfections comprising administration to a body in need of such treatmentof an effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation eg whenthe agent is in admixture with a suitable pharmaceutical excipient,diluent or carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice.

Accordingly, in one aspect, the present invention provides apharmaceutical composition or formulation comprising at least onecompound of the invention or a pharmaceutically acceptable derivativethereof in association with a pharmaceutically acceptable excipient,diluent and/or carrier. The excipient, diluent and/or carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

In another aspect, the invention provides a pharmaceutical compositioncomprising, as active ingredient, at least one compound of the inventionor a pharmaceutically acceptable derivative thereof in association witha pharmaceutically acceptable excipient, diluent and/or carrier for usein therapy, and in particular, in the treatment of human or animalsubjects suffering from a condition susceptible to amelioration by anantimicrobial compound.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable excipient, diluentand/or carrier (including combinations thereof).

There is further provided by the present invention a process ofpreparing a pharmaceutical composition, which process comprises mixingat least one compound of the invention or a pharmaceutically acceptablederivative thereof, together with a pharmaceutically acceptableexcipient, diluent and/or carrier.

The compounds of the invention may be formulated for administration inany convenient way for use in human or veterinary medicine and theinvention therefore includes within its scope pharmaceuticalcompositions comprising a compound of the invention adapted for use inhuman or veterinary medicine. Such compositions may be presented for usein a conventional manner with the aid of one or more suitableexcipients, diluents and/or carriers. Acceptable excipients, diluentsand carriers for therapeutic use are well known in the pharmaceuticalart, and are described, for example, in Remington's PharmaceuticalSciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice ofpharmaceutical excipient, diluent and/or carrier can be selected withregard to the intended route of administration and standardpharmaceutical practice. The pharmaceutical compositions may compriseas—or in addition to—the excipient, diluent and/or carrier any suitablebinder(s), lubricant(s), suspending agent(s), coating agent(s),solubilizing agent(s).

Preservatives, stabilizers, dyes and even flavoring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also beused in combination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e. g. asa carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described in WO91/11172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention may beprepared by processes known in the art, for example see InternationalPatent Application No. WO 02/00196 (SmithKline Beecham).

The routes for administration (delivery) include, but are hot limitedto, one or more of: oral (e. g. as a tablet, capsule, or as aningestable solution), topical, mucosal (e. g. as a nasal spray oraerosol for inhalation), nasal, parenteral (e. g. by an injectableform), gastrointestinal, intraspinal, intraperitoneal, intramuscular,intravenous, intrauterine, intraocular, intradermal, intracranial,intratracheal, intravaginal, intracerebroventricular, intracerebral,subcutaneous, ophthalmic (including intravitreal or intracameral),transdermal, rectal, buccal, epidural and sublingual.

There may be different composition/formulation requirements depending onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestable solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavoring or coloring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

It is to be understood that not all of the compounds need beadministered by the same route. Likewise, if the composition comprisesmore than one active component, then those components may beadministered by different routes.

The compositions of the invention include those in a form especiallyformulated for parenteral, oral, buccal, rectal, topical, implant,ophthalmic, nasal or genito-urinary use. For some applications, theagents of the present invention are delivered systemically (such asorally, buccally, sublingually), more preferably orally. Hence,preferably the agent is in a form that is suitable for oral delivery.

If the compound of the present invention is administered parenterally,then examples of such administration include one or more of:intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the agent; and/or byusing infusion techniques.

For parenteral administration, the compound is best used in the form ofa sterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

The compounds according to the invention may be formulated for use inhuman or veterinary medicine by injection (e.g. by intravenous bolusinjection or infusion or via intramuscular, subcutaneous or intrathecalroutes) and may be presented in unit dose form, in ampoules, or otherunit-dose containers, or in multi-dose containers, if necessary with anadded preservative. The compositions for injection may be in the form ofsuspensions, solutions, or emulsions, in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing,solubilizing and/or dispersing agents. Alternatively the activeingredient may be in sterile powder form for reconstitution with asuitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compounds of the invention can be administered (e. g. orally ortopically) in the form of tablets, capsules, ovules, elixirs, solutionsor suspensions, which may contain flavoring or coloring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications.

The compounds of the invention may also be presented for human orveterinary use in a form suitable for oral or buccal administration, forexample in the form of solutions, gels, syrups, mouth washes orsuspensions, or a dry powder for constitution with water or othersuitable vehicle before use, optionally with flavoring and coloringagents. Solid compositions such as tablets, capsules, lozenges,pastilles, pills, boluses, powder, pastes, granules, bullets or premixpreparations may also be used. Solid and liquid compositions for oraluse may be prepared according to methods well known in the art. Suchcompositions may also contain one or more pharmaceutically acceptablecarriers and excipients which may be in solid or liquid form.

The tablets may contain excipients such as microcrystalline cellulose,lactose, sodium citrate, calcium carbonate, dibasic calcium phosphateand glycine, disintegrants such as starch (preferably corn, potato ortapioca starch), sodium starch glycollate, croscarmellose sodium andcertain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, stearicacid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the agent may becombined with various sweetening or flavoring agents, coloring matter ordyes, with emulsifying and/or suspending agents and with diluents suchas water, ethanol, propylene glycol and glycerin, and combinationsthereof.

The compounds of the invention may also be administered orally inveterinary medicine in the form of a liquid drench such as a solution,suspension or dispersion of the active ingredient together with apharmaceutically acceptable carrier or excipient.

The compounds of the invention may also, for example, be formulated assuppositories e.g. containing conventional suppository bases for use inhuman or veterinary medicine or as pessaries e.g. containingconventional pessary bases.

The compounds according to the invention may be formulated for topicaladministration, for use in human and veterinary medicine, in the form ofointments, creams, gels, hydrogels, lotions, solutions, shampoos,powders (including spray or dusting powders), pessaries, tampons,sprays, dips, aerosols, drops (e.g. eye ear or nose drops) or pour-ons.

For application topically to the skin, the agent of the presentinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water.

Alternatively, it can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

The compounds may also be dermally or transdermally administered, forexample, by use of a skin patch.

For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

As indicated, the compound of the present invention can be administeredintranasally or by inhalation and is conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurized container, pump, spray or nebuliser with the use of asuitable propellant, e. g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134AT″″) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Thepressurized container, pump, spray or nebuliser may contain a solutionor suspension of the active compound, e. g. using a mixture of ethanoland the propellant as the solvent, which may additionally contain alubricant, e. g. sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound and a suitable powder base such as lactose or starch.

For topical administration by inhalation the compounds according to theinvention may be delivered for use in human or veterinary medicine via anebuliser.

The compounds of the invention may also be used in combination withother therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

When a compound of the invention or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art. It will beappreciated that the amount of a compound of the invention required foruse in treatment will vary with the nature of the condition beingtreated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.The compounds of the present invention may for example be used fortopical administration with other active ingredients such ascorticosteroids or antifungals as appropriate.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

The compositions may contain from 0.01-99% of the active material. Fortopical administration, for example, the composition will generallycontain from 0.01-10%, more preferably 0.01-1% of the active material.

Typically, a physician will determine the actual dosage which will bemost suitable for an individual subject. The specific dose level andfrequency of dosage for any particular individual may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the individual undergoing therapy.

For oral and parenteral administration to humans, the daily dosage levelof the agent may be in single or divided doses.

For systemic administration the daily dose as employed for adult humantreatment it will range from 2-100 mg/kg body weight, preferably 5-60mg/kg body weight, which may be administered in 1 to 4 daily doses, forexample, depending on the route of administration and the condition ofthe patient. When the composition comprises dosage units, each unit willpreferably contain 200 mg to 1 g of active ingredient. The duration oftreatment will be dictated by the rate of response rather than byarbitrary numbers of days.

Compounds of general formula (I) and salts thereof may be prepared bythe general methods outlined hereinafter, said methods constituting afurther aspect of the invention. In the following description, thegroups R¹ to R³³, A, B, X, Y, U, W, d, e, f, g, h, i, j, k, m, n, p, q,r, s, t, v, w and z have the meaning defined for the compounds offormula (I) unless otherwise stated.

The groups R^(11a), B^(a)R^(11a) and X^(a)R^(11a) are R¹¹, BR¹¹ and XR¹¹as defined for formula (I) or groups convertible to R¹¹, BR¹¹ and XR¹¹.Conversion of such groups typically arises if a protecting group isneeded during the reactions described below. A comprehensive discussionof the ways in which such groups may be protected and methods forcleaving the resulting protected derivatives is given by for example T.W. Greene and P. G. M Wuts in Protective Groups in Organic Synthesis2^(nd) ed., John Wiley & Son, Inc 1991 and by P. J. Kocienski inProtecting Groups, Georg Thieme Verlag 1994 which are incorporatedherein by reference. Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl andacetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz, and9-fluorenylmethoxycarbonyl (Fmoc)), aliphatic urethane protecting groups(e.g. t-butyloxycarbonyl (Boc), isopropyloxycarbonyl andcyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl,trityl and chlorotrityl). Examples of suitable oxygen protecting groupsmay include for example alkyl silyl groups, such as trimethylsilyl ortert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl ortert-butyl; or esters such as acetate. Hydroxy groups may be protectedby reaction of for example acetic anhydride, benzoic anhydride or atrialkylsilyl chloride in an aprotic solvent. Examples of aproticsolvents are dichloromethane, N,N-dimethylformamide, dimethylsulfoxide,tetrahydrofuran and the like.

Compounds of formula (I) wherein U is —N(R³⁰)— may be prepared byreaction of a 4″ aldehyde compound of formula (II) wherein A, R², R³, R⁴and R⁵ may be suitably protected, for example by cyclic protectionbetween the 9 and 12 positions when A is —C(O)— and d′ is an integerfrom 1 to 5, with a suitable protected derivative of the amine (IIIa) or(IIIb), followed where necessary by subsequent removal of the hydroxylprotecting group R² and conversion of the B^(a)R^(11a) or R^(11a) groupto BR¹¹ or R¹¹.

The reductive amination reaction is preferably carried out in a solventsuch as methanol and DMF. A suitable reducing agent is, for example,sodium cyanoborohydride.

Compounds of formula (II) where d′ is 1 or 2 may be prepared fromsuitably protected compounds of formula (IV) by hydroboration with9-BBN, or other suitable boranes, followed by treatment with peroxideand then oxidation (d′=2), or by osmium tetroxide/peridoate cleavage(d′=1). Compounds of formula (IV) can be formed by palladium-catalyzedallylation of suitably protected 4″ hydroxy compounds.

In another embodiment of the invention, compounds of formula (I) whereinU is a group selected from —N(R³⁰)— and —S—, may be prepared by reactionof compounds of formula (V)

wherein d is an integer from 2 to 6 and L is a suitable leaving-group,with X^(a)R^(11a) (VI) in which U is a group selected from —N(R³⁰)— and—S—. The reaction is preferably carried out in a solvent such as ahalohydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuranor dimethoxyethane), acetonitrile or ethyl acetate and the like,dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-pyrrolidone and inthe presence of a base, followed, if desired, by removal of the hydroxylprotecting group R² and conversion of the X^(a)R^(11a) group to XR¹¹.Examples of the bases which may be used include organic bases such asdiisopropylethylamine, triethylamine and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and inorganic bases such aspotassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide,sodium hydride, potassium hydride and the like. Suitable leaving groupsfor this reaction include halide (e.g. chloride, bromide or iodide) or asulfonyloxy group (e.g. tosyloxy or methanesulfonyloxy).

Compounds of formula (I) may be converted into other compounds offormula (I). Thus compounds of formula (I) wherein U or B is —S(O)_(z)—and z is 1 or 2 may be prepared by oxidation of the correspondingcompound of formula (I) wherein z is 0. The oxidation is preferablycarried out using a peracid, e.g. peroxybenzoic acid, followed bytreatment with a phosphine, such as triphenylphosphine. The reaction issuitably carried out in an organic solvent such as methylene chloride.Compounds of formula (I) wherein U or B is —N(R³⁰)— and R³⁰ is C₁₋₄alkylcan be prepared from compounds wherein R³⁰ is hydrogen by reductivealkylation.

In another embodiment of the invention, compounds of formula (I) whereinU is —O—, may be prepared by reaction of compounds of formula (VII)

with a suitable compound of formula X^(a)R^(11a), in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium.

In a further embodiment of the invention, compounds of formula (I)wherein U is —C(O)N(R³⁰)—, may be prepared by reaction of compounds offormula (VIII)

with a suitable amine compound.

Compounds of formula (II) wherein A is —C(O)NH— or —NHC(O)—, R⁴ or R⁵are hydroxy, R³ is hydrogen and R⁶ is hydrogen are known compounds orthey may be prepared by analogous methods to those known in the art.Thus they can be prepared according to the procedures described in EP507595 and EP 503932.

Compounds of formula (II), wherein A is —C(O)NH— or —NHC(O)—, R⁴ or R⁵are hydroxy and R³ is C₁₋₄alkyl or C₃₋₆alkenyl optionally substituted by9 to 10 membered fused bicyclic heteroaryl and R⁶ is hydrogen are knowncompounds or they may be prepared by analogous methods to those known inthe art. Thus they can be prepared according to the procedures describedin WO 9951616 and WO 0063223.

Compounds of formula (II), wherein A is —C(O)NH—, R⁴ and R⁵ takentogether with the intervening atoms form a cyclic group having thefollowing structure:

R³ is C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to 10membered fused bicyclic heteroaryl and R⁶ is hydrogen are knowncompounds or they may be prepared by analogous methods to those known inthe art. Thus they can be prepared according to the procedures describedin U.S. Pat. No. 6,262,030.

Compounds of formula (II), wherein A is —C(O)—, —C(O)NH—, —NHC(O)—,—N(R⁷)—CH₂—, —CH₂—N(R⁷)— or —CH(NR⁸R⁹)—, R⁴ or R⁵ are hydroxy or R⁴ andR⁵ taken together with the intervening atoms form a cyclic group havingthe following structure:

wherein Y is a bivalent radical selected from —O— and —N(R¹³)—, and R³is C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to 10 memberedfused bicyclic heteroaryl are known compounds or they may be prepared byanalogous methods to those known in the art. Thus they can be preparedaccording to the procedures described in EP 307177, EP 248279, WO0078773, WO 9742204.

Compounds of formula (II), wherein A is —C(O)NH—, —NHC(O)—, —N(CH₃)—CH₂—or —CH₂—N(CH₃)—, R⁴ or R⁵ are hydroxy or R⁴ and R⁵ taken together withthe intervening atoms form a cyclic group having the followingstructure:

and R⁶ is hydrogen are known compounds or they may be prepared byanalogous methods to those known in the art. Thus they can be preparedaccording to the procedures described in EP 508699 and J. Chem. Res.Synop (1988 pages 152-153), U.S. Pat. No. 6,262,030.

Compounds of formula (II), wherein A is —C(═NR¹⁰)—, R⁴ or R⁵ are hydroxyor R⁴ and R⁵ taken together with the intervening atoms form a cyclicgroup having the following structure:

and R⁶ is hydrogen, are known compounds or they may be prepared byanalogous methods to those known in the art. Thus they can be preparedaccording to the procedures described in EP 284203.

Compounds of formula (II), wherein A is —C(O)—, R⁴ and R⁵ taken togetherwith the intervening atoms form a cyclic group having the followingstructure:

R⁶ is hydrogen and R³ is C₁₋₄ alkyl may be prepared by decarboxylationof a compound of formula (IX), wherein R³⁴ is amino protecting groupfollowed, if required, by removal of the protecting group R² or R³⁴.

The decarboxylation may be carried out in the presence of a lithium saltsuch as lithium chloride, preferably in an organic solvent such asdimethylsulfoxide.

Compounds of formula (II), wherein A is —C(O)—, R⁴ and R⁵ taken togetherwith the intervening atoms form a cyclic group having the followingstructure:

and R₃ is C₁₋₄ alkyl may be prepared according to the proceduresdescribed in WO 02/50091 and WO 02/50092.

In order that the invention may be more fully understood the followingexamples are given by way of illustration only.

The following abbreviations are used in the text: Ac for acetyl, Ac₂Ofor acetic anhydride, 9-BBN for 9-borabicyclo[3.3.1]nonane, BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, BOC for t-butoxycarbonyl,DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, DCM for dichloromethane,DIPEA for N,N-diisopropylethylamine. DMF for N,N-dimethylformamide, DMSOfor dimethyl sulfoxide, Et₂O for diethyl ether, EtOAc for ethyl acetate,EtOH for ethanol, HBTU for2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, HOAc for acetic acid, LDA for lithiumdiisopropylamide, MeCN for acetonitrile, MeOH for methanol and THF fortetrahydrofuran.

EXAMPLES

2′-O-Acetyl-azithromycin-11,12-carbonate may be prepared by theprocedure described by S. Djokic et al. In J. Chem. Res. (S) 1988, 152.

Nomenclature

In the Examples, compounds of formula (I) in which R¹¹ is a tricyclicheterocyclic group are referred to using the numbering system below:

1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline Intermediate 1:6-[(2-Aminoethyl)amino]-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid

7-Chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-quinoline-3-carboxylicacid (56.3 g) and ethylenediamine (36 g) were dissolved inN,N-dimethylacetamide (650 mL) at 100° C. and stirred for 8.5 h at 115°C. Water (700 mL) was added to the reaction mixture cooled at roomtemperature. The reaction mixture was stirred at room temperature for 2h, cooled at 0-5° C. and stirred for 1 h. The precipitate obtained wasfiltered, washed with cold water, cold EtOH, and dried at 110° C. underreduced pressure for 1 h. The crude product was treated with HCl (6%aqueous solution) heating for 1 h in the presence of charcoal. Afterfiltration, the solution was cooled to 35-40° C. and a firstprecipitation happened. The precipitate was filtered, washed with waterand dried at 110° C. for 1 h. The title compound (6.4 g) was obtained asthe hydrochloride salt. The hydrochloride salt was then converted to thefree base using standard conditions; ESMS m/z 320 [M−H]⁻.

Intermediate 2:6-(2-Amino-ethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acidhydrochloride a)6-(2-Dibenzylamino-ethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 2-dibenzylamino-ethyl ester

1-Ethyl-6-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (GB1433774) (1.4 g, 6 mmol) was dissolved in dry DMF (80 mL). To this wasadded potassium carbonate (5 g, 36 mmol) anddibenzyl-(2-chloroethyl)amine hydrochloride (4.37 g, 14.8 mmol). Themixture was heated at 65° C. with stirring for 72 h, then allowed tocool overnight. The mixture was evaporated to a small volume, dilutedwith water and extracted with ethyl acetate (×2). The combined organicextracts were washed with brine, dried and evaporated under reducedpressure to give a dark viscous oil (4.9 g). This residue was purifiedby chromatography on silica gel (100 g), eluting with 0.2-3.8% methanolin dichloromethane, to give the title compound as a brown solid (2.46 g,60%); ESMS m/z 680 [M+H]⁺ (100%).

b)6-(2-Dibenzylamino-ethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid sodium salt

Intermediate 2a (2.44 g, 3.59 mmol) was dissolved in methanol (25 mL)and 1,4-dioxane (25 mL), then aqueous sodium hydroxide (0.4N, 8.75 mL,3.5 mmol) was added. Stirred for 40 h then a little more sodiumhydroxide was added and stirring continued for a further 72 h. Excesssolid carbon dioxide was then added and the mixture evaporated todryness under reduced pressure. Trituration with diethyl ether gave thetitle compound as a pale brown powder (1.382 g, 84%); ESMS m/z 457[M+H]⁺ for the free acid (100%).

c) 6-(2-Amino-ethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid

Intermediate 2b (1.38 g, 2.89 mmol) was dissolved in 1,4-dioxane (80mL), water (40 mL) and hydrochloric acid (2N, 2.9 mL, 5.8 mmol). Thissolution was hydrogenated over 20% palladium(II) hydroxide on carbon(0.6 g) at 50 psi for 18 h. The mixture was filtered through kieselguhr,washing well with water. The filtrate was then evaporated to drynessunder reduced pressure to give the title compound as a pale yellow solid(1 g, 94%) (containing one equivalent of sodium chloride); ESMS m/z 277[M+H]⁺ for free acid (100%).

Intermediate 3:6-(2-Aminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid trifluoroacetate salt a)6-Bromo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethylester

A mixture of potassium carbonate (2.95 g, 21.2 mmol) and6-bromoquinolone-3-carboxylic acid (2.84 g, 10.6 mmol) indimethylformamide (25 mL) was heated to 40° C. under argon for 10minutes and iodoethane (3.4 mL, 42.4 mmol) was added. After 14 h themixture was cooled and the DMF evaporated. The residue was treated withwater (40 mL), cooled to 5° C. and filtered under vacuum. The resultantcream-colored solid was dried under vacuum to yield the title compound;¹H NMR δ [(CD₃)₂SO] 1.41 (3H, t, J=7.1 Hz), 1.54 (3H, J=7.2 Hz), 4.24(2H, q, J=7.2 Hz), 4.40 (2H, q, J=7.1 Hz), 7.34 (1H, d, J=9 Hz), 7.76(1H, dd, J=2.4 & 9 Hz), 8.65 (1H, d, J=2.4 Hz), 8.49 (1H, s).

b)6-(2-t-Butoxycarbonylaminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

A mixture of N-Boc-cysteinamine (0.35 g, 2 mmol), Intermediate 3a (0.32g, 1 mmol) and potassium carbonate (0.28 g, 2 mmol) was heated in DMSO(10 mL) for 16 h at 90° C. After chromatography over silica gel elutingwith dichloromethane containing an increasing concentration ofmethanol/ammonium hydroxide the title compound was obtained as a whitesolid; ESMS m/z 421 [M+H]⁺ (100%).

c)6-(2-t-Butoxycarbonylaminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid sodium salt

To a solution of Intermediate 3b (0.11 g, 0.27 mmol) in THF (2 mL) wasadded 2M sodium hydroxide (0.13 mL, 0.27 mmol). After stirring for 16 hat room temperature the mixture was saturated with carbon dioxide andthe solvent evaporated. The residue was treated with methanol (10 mL),filtered and the solvent evaporated to yield the title compound as apale yellow solid; ESMS m/z 393 [M+H]⁺ (25%).

d)6-(2-Aminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid trifluoroacetate salt

To Intermediate 3c (0.068 g, 0.17 mmol) was added trifluoroacetic acid(1 mL). After 1 h the solvent was evaporated to yield a green gum; ¹ HNMR δ [(CD₃)₂SO] 1.54 (3H, t, J=7.2 Hz), 3.20 (2H, q, J=6.8 Hz), 3.38(2H, t, J=6.8 Hz), 4.56 (2H, q, J=7.2 Hz), 7.98-7.90 (2H, m), 8.40 (1H,d, J=2.0 Hz), 8.94 (1H, s).

Intermediate 4:6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acidtrifluoroacetate salt a)1-Ethyl-6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester

A mixture of 1,4-dihydro-6-iodo-4-oxo-quinoline-3-carboxylic acid (J.Ellis et al, Aust. J. Chem., 1973, 26, 907) (3.15 g, 10 mmol), potassiumcarbonate (6.9 g, 50 mmol) and iodoethane (15.6 g, 100 mmol) in dry DMFwas heated at 70° C. with vigorous stirring. After 16 h the mixture wascooled and diluted with ethyl acetate. The resultant mixture was washedwith water and the organic phase separated, dried and evaporated toyield the title compound as pale yellow solid, ¹H NMR δ (CDCl₃) 1.41(3H, t, J=7.1 Hz), 1.54 (3H, t, J=7.3 Hz), 4.23 (2H, q, J=7.2 Hz), 4.40(2H, q, J=7.1 Hz), 7.20 (1H, d, J=8.9 Hz), 7.95 (1H, dd, J=2.1 & 8.9Hz), 8.48 (1H, s), 8.86 (1H, d, J=2.1 Hz).

b)6-(3-t-Butoxycarbonylamino-prop-1-ynyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

Intermediate 4a (0.371 g, 1 mmol), copper (I) iodide (26 mg, 0.13 mmol)and triethylamine (6.16 mL, 44 mmol) were suspended in dry acetonitrile(22 mL). The light green suspension was heated to 50° C. whilst argonwas bubbled through. After 20 min,dichlorobis(triphenylphosphine)palladium (II) (0.026 g, 0.0379 mmol) andt-butoxycarbonylpropargylamine (0.264 g, 1.7 mmol) were added and thebrown suspension was heated under reflux. After 2 h the reaction mixturewas cooled, filtered and concentrated. The residue was taken up indichloromethane and washed with water. The organic phase was dried andconcentrated to provide a brown oil which was purified by chromatographyon silica gel eluting with 0-2.5% (9:1 MeOH/20 M ammonia) indichloromethane to yield the title compound as a yellow solid; ESMS m/z399 (M+H⁺).

c)6-(3-t-Butoxycarbonylaminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

Intermediate 4b (0.366 mg, 0.77 mmol) in dichloromethane (10 mL) washydrogenated over 10% palladium on charcoal (50 mg) for 16 h. Theresultant mixture was filtered and the solvent evaporated to give thetitle compound as a yellow oil; ESMS m/z 403 [M+H]⁺.

d) 6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

Using a similar procedure to that described in Intermediate 3d,Intermediate 4c (355 mg, 0.88 mmol) gave the title compound as a yellowoil; ESMS m/z 303 [M+H]⁺.

e) 6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid sodium salt

Using a similar procedure to that described in Intermediate 3c,Intermediate 4d (250 mg, 0.83 mmol) gave the title compound as a yellowsolid; ESMS m/z 275 [M+H]⁺.

f) 6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid trifluoroacetate salt

Intermediate 4e (0.06 g, 0.2 mmol) was subjected to reverse phase HPLCpurification to give the title compound as white solid; ¹H NMR δ[(CD₃)₂SO] 1.54 (3H, t, J=7.2 Hz), 2.0-2.1 (2H, m), 2.9-3.0 (4H, m),4.58 (2H, q, J=7.2 Hz), 7.85,(1H, dd, J=2.2 & 8.8 Hz), 7.96 (1H, d,J=8.8 Hz), 8.36 (1H, d, J=1.8 Hz), 8.97 (1H, s).

Intermediate 5:9-(2-Amino-ethoxy)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid hydrochloride a)9-(2-Dibenzylamino-ethoxy)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid 2-dibenzylamino-ethyl ester

9-Hydroxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid (GB1417129) (0.905 g, 3.69 mmol) was suspended in dry DMF (50 mL).To this was added potassium carbonate (3.06 g, 22 mmol) anddibenzyl-(2-chloroethyl)amine hydrochloride (2.37 g, 8 mmol). Themixture was heated at 60° C. for 16 h, then more potassium carbonate(0.55 g) and dibenzyl-(2-chloroethyl)amine hydrochloride (1.18 g, 4mmol) were added. After a further 25 h at 75° C. the mixture wasevaporated. The residue was diluted with water and extracted with ethylacetate (×3). The combined organic extracts were washed with brine,dried and evaporated under reduced pressure. The crude product (4.0 g)was purified by chromatography on silica gel (100 g), eluting with 0-4%methanol in dichloromethane, to give the title compound (2.25 g, 89%);ESMS m/z 692 [M+H]⁺ (100%).

b)9-(2-Dibenzylamino-ethoxy)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid sodium salt

Intermediate 5a (2.22 g, 3.21 mmol) was dissolved in methanol (30 mL)and 1,4-dioxane (20 mL), and treated with aqueous sodium hydroxide(0.4N, 8.03 mL, 3.21 mmol). The mixture was stirred for 88 h at 20° C.Solid carbon dioxide was then added and the mixture evaporated todryness under reduced pressure. The residue was triturated with diethylether to give the title compound as a white powder (1.6 g, 100%); ESMSm/z 469 [M+H]⁺ for free acid (100%).

c)9-(2-Amino-ethoxy)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid hydrochloride

Intermediate 5b (0.8 g, 1.63 mmol) was dissolved in 1,4-dioxane (100mL), water (15 mL) and hydrochloric acid (2N, 1.6 mL, 3.2 mmol). Thissolution was hydrogenated over 20% palladium (II) hydroxide on carbon(0.4 g) at 50 psi for 42 h. The mixture was diluted with water andfiltered through kieselguhr, washing well with water. The filtrate wasthen evaporated to dryness under reduced pressure to give the titlecompound as an off-white solid (0.54 g, 87%) (containing one equivalentof sodium chloride); ESMS m/z 289 [M+H]⁺ for free acid (100%).

Intermediate 6:7-(2-Amino-ethylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1.8]naphthyridine-3-carboxylicacid trifluoroacetate a)7-(2-tert-Butoxycarbonylamino-ethylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid ethyl ester

7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid ethyl ester (2.20 g, 7.37 mmol) in THF (20 mL) and MeCN (20 mL) wastreated with triethylamine (3.07 mL, 22.0 mmol), followed by(2-amino-ethyl)-carbamic acid tert-butyl ester (1.41 g, 8.80 mmol) andthe mixture heated to 70° C. After 26 h (2-amino-ethyl)-carbamic acidtert-butyl ester (300 mg, 1.87 mmol) was added. After a further 15 h theheating was stopped and the solvent removed in vacuo. The residue wastaken up in ethyl acetate, washed with water, dried filtered, andconcentrated in vacuo to give a residue which was purified bychromatography (silica gel, 30-100% ethyl acetate in petroleum ether(b.p. 40-60° C.)) to give the title compound (2.89 g); ESMS m/z 423[M+H]⁺.

b)7-(2-tert-Butoxycarbonylamino-ethylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

To Intermediate 6a (2.89 g, 6.84 mmol) in THF (30 mL) was added 2 Naqueous sodium hydroxide (3.4 mL, 6.8 mmol), and the mixture stirred atroom temperature. After 24 h 2 N aqueous sodium hydroxide (0.6 mL, 1.2mmol) was added and stirring continued for a further 24 h. The solventwas then removed in vacuo, and the residue taken up in water (10 mL).Solid carbon dioxide was added, and the resulting precipitate filteredoff and dried in vacuo to give the title compound (2.65 g); ESMS m/z 395[M+H]⁺.

c)7-(2-Amino-ethylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid trifluoroacetate

Intermediate 6b (2.65 g, 6.72 mmol) was suspended in dichloromethane (30mL), trifluoroacetic acid (15 mL) added, and the solution stirred for 35min. The mixture was concentrated in vacuo, and again from toluene, andagain from hexane to give the title compound as a tan powder (2.92 g);ESMS m/z 295 [M+H]⁺.

Intermediate 7:2′-O-Acetyl-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycin A11,12-carbamate

6-O-Methyl-11-desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate(W. R. Baker et al., J. Org. Chem., 1988, 53(10), 2340-5) (0.87 g) wasdissolved in DCM (20 mL) and acetone (3 mL). Solid NaHCO₃ (0.6 g) andAc₂O (0.6 mL) were added and the reaction mixture was stirred for 1 h,then DCM (50 mL) and water (50 mL) were added. The organic phase wasseparated, washed with brine (20 mL), dried over K₂CO₃, filtered andconcentrated under reduced pressure, affording the title compound (0.875g); ESMS m/z 829 [MH]⁺.

Intermediate 8:6-((Z)-3-tert-Butoxycarbonyloxyprop-1-enyl)-1,4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylicacid ethyl ester a)1,4-Dihydro-1-ethyl-6-iodo-4-oxo-quinoline-3-carboxylic acid ethyl ester

A mixture of 1,4-dihydro-6-iodo-4-oxo-quinoline-3-carboxylic acid (J.Ellis, E. Gellert, J. Robson, Aust. J. Chem., 1973, 26, 907) (3.15 g, 10mmol), potassium carbonate (6.9 g, 50 mmol) and iodoethane (15.6 g, 100mmol) in dry DMF was heated at 70° C. with vigorous stirring. After 16 hthe mixture was cooled and diluted with ethyl acetate. The resultantmixture was washed with water and the organic phase separated, dried andevaporated to yield the title compound as pale yellow solid, ¹H NMR δ(CDCl₃) 1.41 (3H, t, J=7.1 Hz), 1.54 (3H, t, J=7.3 Hz), 4.23 (2H, q,J=7.2 Hz), 4.40 (2H, q, J=7.1 Hz), 7.20 (1H, d, J=8.9 Hz), 7.95 (1H, dd,J=2.1 & 8.9 Hz), 8.48 (1H, s), 8.86 (1H, d, J=2.1 Hz).

b)6-(3-Hydroxyprop-1-ynyl)-1,4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylicacid ethyl ester

Intermediate 8a (3.71 g, 10 mmol), copper (I) iodide (0.209 g, 1.1 mmol)were suspended in dry acetonitrile (100 mL) and triethylamine (49 mL).The light green suspension was heated to 50° C. whilst argon was bubbledthrough. After 20 min, dichlorobis(triphenylphosphine)palladium (II)(0.21 g, 0.3 mmol) and propargyl alcohol (0.92 mL, 17 mmol) were addedand the brown suspension was heated under argon at 50° C. for 3.5 h. Thecrude product was purified by chromatography on silica gel eluting witha gradient of dichloromethane in hexane followed by a gradient ofmethanol in dichloromethane. Product containing fractions wereevaporated to dryness and the residue dissolved in chloroform andfiltered. The filtrate was evaporated to dryness to yield the titlecompound as a beige solid, (1.62 g, 54%); ESMS m/z 300 [M+H]⁺.

c)6-((Z)-3-Hydroxyprop-1-enyl)-1,4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylicacid ethyl ester

Intermediate 8a (0.39 g, 1.3 mmol) in ethanol (10 mL) and 1,4-dioxan (5mL) was hydrogenated at 20° C. and 1 atm over Lindlar catalyst (0.05 g).After 5 h, dichloromethane (10 mL) was added, and the hydrogenationcontinued for 18 h. The catalyst was filtered off and washed well withethanol/dichloromethane. The combined filtrates were evaporated todryness and the residue taken up in ethanol (4 mL) and dichloromethane(12 mL), and rehydrogenated at 20° C. and 1 atm over Lindlar catalyst(0.2 g) for 3 h. The catalyst was filtered off and washed well withethanol/dichloromethane. The combined filtrates were evaporated todryness to give the title product as a white solid, (0.394 g) ESMS m/z302 [M+H]⁺.

d)6-((Z)-3-tert-Butoxycarbonyloxyprop-1-enyl)-1,4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylicacid ethyl ester

Intermediate 8a (0.393 g, 1.3 mmol) in dichloromethane (10 mL) wastreated with di-tert-butyl dicarbonate (0.327 g, 1.5 mmol) andN-methylimidazole (0.01 g). After 4 d at 20° C. the crude product waspurified by chromatography on silica gel eluting with a gradient ofethyl acetate in hexane to give the title product, (0.40 g, 77%). ¹H NMRδ (CDCl₃) 1.42 (3H, t, J=7.1 Hz), 1.49 (9H, s), 1.51 (3H, t, J=7.2 Hz),4.26 (2H, q, J=7.2 Hz), 4.41 (2H, q, J=7.1 Hz), 4.89 (2H, dd, J=6.4, 2.0Hz), 5.93 (1H, dt, J=11.8, 6.4Hz), 6.73 (1H, bd, J=11.8 Hz), 7.44 (1H,d, J=8.8 Hz), 7.58 (1H, dd, J=8.8, 2.2 Hz), 8.35 (1H, d, J=2.2 Hz), 8.49(1H, s).

Intermediate 9:6-(3-Aminopropyl)-1-ethyl-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid trifluoroacetate a) Diethyl{[(4-iodo-3-methylphenyl)amino]methylidene}propanedioate

4-iodo-3-methylaniline (5.75 g) was suspended in diethylethoxymethylenemalonate (5.5 mL). The mixture was heated at 130° C. for2.5 h. After cooling to ˜90° C., hexane was added and the mixturestirred while cooling to room temperature. The product crystallized out,and was filtered off, washing well with more hexane. The solid was driedin vacuo to yield the title compound as a pale grey powder (7.947 g); ¹HNMR δ (CDCl₃) 1.33 (3H, t), 1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q),4.3 (2H, q), 6.69 (1H, dd), 7.01 (1H, d), 7.75 (1H, d), 8.46 (1H, d),and 10.95 (1H, br d).

b) Ethyl 6-iodo-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate

Intermediate 9a (8.73 g) was suspended in Dowtherm (30 mL) then heatedat 250° C. for 1 h. The mixture cooled, petroleum ether added, and thesolid filtered off, washing well with more petroleum ether. The solidwas dried in vacuo to give the title compound and the 7-methyl isomer asa pale grey powder (7.8 g).

c) Ethyl1-ethyl-6-iodo-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate

Intermediate 9b (3.57 g) was suspended in DMF (25 mL), potassiumcarbonate (1.66 g) and iodoethane (3.2 mL) added, and the mixture heatedat 55° C.-60° C. for 89 h. More iodoethane (2×2 mL) being added after 64and 69 h. The mixture was evaporated, diluted with water and extractedwith ethyl acetate (×7). The combined organic extracts were washed withaqueous sodium thiosulphate solution then brine, dried and evaporated.The residue was purified by chromatography on silica gel (100 g),eluting with 40-100% ethyl acetate in petroleum ether followed by 5%methanol in dichloromethane, to give the title compound as a pale brownsolid (0.492 g); ESMS m/z 386 [M+H]⁺.

d) Ethyl6-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-propyn-1-yl]-1-ethyl-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate

Using a similar procedure to that described in Intermediate 4b,Intermediate 9c (0.485 g) and t-butoxycarbonylpropargylamine (0.332 g)gave the title compound as a yellow solid (0.62 g); ESMS m/z 413 [M+H]⁺.

e) Ethyl6-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-1-ethyl-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate

Intermediate 9d (0.52 g) in DCM (30 mL) was treated with 10% Pd/C (0.4g). The mixture filtered then hydrogenated over 10% Pd/C (0.4 g) for 1h. The resultant mixture was filtered and the solvent evaporated to givethe title compound as a yellow foam (0.58 g); ESMS m/z 417 [M+H]⁺.

f)6-[3-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)propyl]-1-ethyl-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid

Using a similar procedure to that described in Intermediate 6b,Intermediate 9e (0.524 g) was reacted to give the title compound as, acream powder (0.457 g); ESMS m/z 389 [M+H]⁺.

g)6-(3-Aminopropyl)-1-ethyl-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid trifluoroacetate

Using a similar procedure to that described in Intermediate 6c,Intermediate 9f (0.453 g) was reacted to give the title compound as apale brown powder (0.505 g); ESMS m/z 289 [M+H]⁺.

Intermediate 10:7-(2-Amino-ethylamino)-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylic acida) 4-Chloro-2-propylpyridine

To a solution of LDA (0.13 moles) in THF/hexanes (40 mL/40 mL) at −60°C. under argon was added a solution of 4-chloro-2-picoline (15 g) in THF(250 mL) over 20 min. After a further 30 min at −60° C. iodoethane (10.4mL) in THF (60 mL) was added over 20 min, the reaction stirred at −60°C. for 1.5 h and then allowed to warm to −30° C. The mixture was pouredinto brine and extracted with dichloromethane. After drying (MgSO₄) andpurification by chromatography eluting with dichloromethane in petroleumether (70-100%) followed by dichloromethane containing methanol (0 to5%) the title compound was obtained as a brown oil (12.35 g). ¹H NMR δ(CDCl₃) 0.97 (3H, t), 1.75 (2H, m), 2.75 (2H, t), 7.12 (1H, m), 7.16(1H, d), 8.42 (1H, d).

b) [2-(4-Chloro-pyridin-2-yl)-1-ethoxy-butyl]-malonic acid diethyl ester

To a solution of LDA (87.5 mmoles) in THF/hexanes (40 mL/40 mL) at −60°C. under argon was added a solution of Example 10a (12.31 g) in dry THF(150 mL) over 20 min. After a further 30 min at −60° C. diethylethoxymethylene malonate (18.81 g) in THF (40 mL)) was added over 20min, the reaction stirred at −60° C. for 1.5 h and then allowed to warmto −30° C. The mixture was poured into brine and extracted with ethylacetate. After drying (MgSO₄) and purification by chromatography elutingwith dichloromethane in petroleum ether (70-100%) followed bydichloromethane containing methanol (0 to 5%) gave the title compound asan oil (27.38 g). ESMS m/z 372 [M+H].

c) 7-Chloro-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylic acid ethyl ester

A solution of Intermediate 10b (27.38 g) and DBU (10 drops) in xylenewas heated at reflux. After 16 h the mixture was cooled and purified bychromatography eluting with dichloromethane containing methanol (0 to10%). The resultant yellow/brown solid was triturated with diethyl etherand filtered to yield the title compound as a yellow solid. ESMS m/z 280(M+H).

d)7-(2-t-Butoxycarbonylaminoethylamino)-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylicacid ethyl ester

A solution of Intermediate 10c (0.63 g), mono Boc ethylene diamine (0.45g) and triethylamine (0.9 mL) in pyridine (15 mL) was heated at 60° C.for 16 h. After evaporation the crude product was purified bychromatography eluting with dichloromethane containing methanol (0 to5%) to give the title product as a yellow solid (0.37 g. ESMS m/z 404(M+H).

e)7-(2-t-Butoxycarbonylaminoethylamino)-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylicacid

Using a similar procedure to that described for the preparation ofIntermediate 6b, Intermediate 10d (0.334 g) gave the title compound asyellow solid ESMS m/z 376(M+H).

f) 7-(2-Aminoethylamino)-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylic acid

Using a similar procedure to that described for the preparation ofIntermediate 6c Intermediate 10e (0.172 g) gave the title compound asyellow solid. ESMS m/z 276 (M+H).

Intermediate 11:6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid trifluoroacetate salt a) Ethyl2-[(2-chloro-5-iodo-3-pyridinyl)carbonyl]-3-(ethylamino)-2-propenoate

5-iodo-2-hydroxypyridine-3-carboxylic acid (T. R. Elworthy et al., J.Med. Chem., 40, 17, 1997, 2674-2687) (7.95 g) was suspended in thionylchloride (40 mL). DMF (4 drops) was added and the mixture refluxed for 4h. The resultant solution was evaporated to dryness. This acid chloridewas then dissolved in 1,4-dioxane (40 mL) and added dropwise to asolution of ethyl 3-(ethylamino)-2-propenoate (5.15 g) and triethylamine(10.5 mL) in 1,4-dioxane at 0° C. After 1 h the cooling bath wasremoved, and the reaction stirred at room temperature for 16 h. Themixture was then evaporated, saturated sodium hydrogen carbonatesolution added, and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried and evaporated to give a darkoil. This was purified by chromatography on silica gel, eluting with33-45% diethyl ether in petroleum ether, to give the title compound(5.35 g); ESMS m/z 409 [M+H]⁺.

b) Ethyl1-ethyl-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Intermediate 11a (4.92 g) was dissolved in DMF (50 mL), potassiumcarbonate (1.662 g) added, and the mixture heated at 50° C. for 16 h and60° C. for 2 h. After evaporation the mixture was diluted with water andextracted with DCM. The combined organic extracts were dried andevaporated to give an oil. This was purified by chromatography on silicagel, eluting with 0-20% diethyl ether in DCM, to give the title compoundas a pale yellow solid (4.33 g); ESMS m/z 373 [M+H]⁺.

c) Ethyl6-[3-(t-butoxycarbonylamino)-1-propyn-1-yl]-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A mixture of Intermediate 11b (2.176 g), copper (I) iodide (115 mg, 0.6mmol) and triethylamine (27.9 mL, 200 mmol) were suspended in dryacetonitrile (40 mL). The light green suspension was heated to 43° C.whilst argon was bubbled through. After 30 min,dichlorobis(triphenylphosphine)palladium (II) (0.127 g, 0.018 mmol) andN-t-butoxycarbonylpropargylamine (1.542 g) were added and the mixturewas heated at 43° C. for 25 min. The reaction mixture was cooled,filtered and concentrated. The residue was taken up in dichloromethaneand washed with water. The organic phase was dried and concentrated toprovide a dark solid which was purified by chromatography on silica geleluting with 0-25% (methanol/diethyl ether [1:24]) in dichloromethane toyield the title compound as a pale yellow solid (1.8 g); ESMS m/z 400[M+H]⁺.

d) Ethyl6-[3-(t-butoxycarbonylamino)-1-propyl]-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Intermediate 11c (0.91 g)) in dichloromethane (50 mL) was treated with10% palladium on carbon (60 mg) and hydrogenated at room temperature andatmospheric pressure for 75 min. The reaction mixture was filtered andconcentrated, and the residue purified by chromatography on silica geleluting with 0-4% methanol in dichloromethane to give the title compoundas an off-white solid (0.83 g); ESMS m/z 404 [M+H]⁺.

e)6-[3-(t-Butoxycarbonylamino)-1-propyl]-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

Intermediate 11d (0.825 g) was dissolved in THF (15 mL), 0.2 N sodiumhydroxide (15 mL) added, and the reaction stirred for 16 h at roomtemperature. The mixture was evaporated to a small volume then solidcarbon dioxide added. The precipitate which formed was filtered off,washed well with water, and dried in vacuo over phosphorus pentoxide togive the title compound as an off-white powder (0.709 g); ESMS m/z 376[M+H]⁺.

f)6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid trifluoroacetate salt

Intermediate 11e (0.72 g) was dissolved in DCM (12 mL), trifluoroaceticacid (4 mL) was added and the reaction stirred under argon at roomtemperature for 0.75 h. The solution was evaporated to dryness, and theresidue triturated with diethyl ether to give, after drying, the titlecompound as an off-white powder (0.859 g). NMR data: ¹H NMR (DMSO-d6)1.43 (3H, t), 1.95 (2H, m), 2.84 (2H, m), 2.92 (2H, t), 4.68 (2H, q),7.78 (3H, br s), 8.63 (1H, d), 8.95 (1H, d), 9.24 (1H, s) and 14.8 (1H,br s).

Intermediate 12:9-(3-Amino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid trifluoroacetate salt a) Diethyl2-((3,4-dihydro-2H-quinolin-1-yl)methylene)malonate

A mixture of tetrahydroquinoline (13.32 g, 100 mmol) and diethylethoxymethylenemalonate (21.62 g, 100 mmol) is heated to 130° C. using aDean-Stark apparatus. After 1 hour the reaction mixture was concentratedto give the title compound as a brown oil. ESMS m/z 304 (MH⁺).

b) Ethyl 1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate

Diethyl 2-((3,4-dihydro-2H-quinolin-1-yl)methylene)malonate (2.5 g, 8.24mmol) was dissolved in polyphosphoric acid and the viscous mixturestirred for 4 hours at 110° C. The reaction mixture was cooled downbefore adding ice. The resulting precipitate was filtered off, washedwith water then dried in a dessicator in the presence of phosphoruspentoxide to give the title compound as a beige solid. ESMS m/z 258(MH⁺). ¹H NMR (DMSO-d₆) δ 8.55(s, 1H), 8.05 (dd, 1H), 7.54 (dd, 1H),7.36 (dd, 1H), 4.27 (q, 2H), 4.22 (q, 2H), 3.00 (t, 2H), 2.10 (tt, 2H),1.28 (t, 3H).

c) Ethyl9-bromo-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate

Ethyl 1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate(290 mg, 1.13 mmol) was dissolved in acetic acid (3 mL) and bromine (197mg, 1.23 mmol) was added dropwise. The reaction was followed by LC/MS,additional bromine (2×197 mg) was added. After 24 hours water was addedand the precipitate was filtered off, washed with diethyl ether thendried in a dessicator in the presence of phosphorus pentoxide to providean orange solid which was purified by chromatography on silica geleluting with 0-1.5% (9:1 MeOH/20 M NH₃) in dichloromethane to yield thetitle compound as a white solid. ESMS m/z 336/338 (MH⁺). ¹H NMR (CDCl₃)δ 8.34(d, 1H), 8.31 (s, 1H), 7.48 (d, 1H), 4.37 (q, 2H), 4.17 (t, 2H),3.03 (t, 2H), 2.23 (tt, 2H), 1.40 (t, 3H).

d) Ethyl9-(3-tert-butoxycarbonylamino-prop-1-ynyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate

A yellow suspension of palladium acetate (73 mg, 0.32 mmol) andtriphenylphosphine (191 mg, 0.72 mmol) in dry tetrahydrofuran (6 mL)under argon was cooled to 0° C. A solution of n-butyllithium (2.5M inhexanes, 284 uL) was added dropwise and after 15 minutes the dark greensuspension is warmed to room temperature for 15 minutes. This suspensionis then cannulated under argon into a white suspension of ethyl9-bromo-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate(337 mg, 1 mmol), copper iodide (84 mg, 0.44 mmol) andt-butoxycarbonylpropargylamine (198 mg, 1.28 mmol) in diethylamine (6mL). The brown suspension is warmed to 45° C. for 2 hours then filteredoff and preabsorbed on silica gel. Chromatography on silica gel elutingwith 0-5% (9:1 MeOH/20 M NH₃) in dichloromethane provided the titlecompound as a brown oil. ESMS m/z 411 (MH⁺). ¹H NMR (CDCl₃) δ 8.23(s,1H), 8.12 (d, 1H), 7.29 (d, 1H), 5.1 (m, 1H), 4.35 (q, 2H), 4.15 (m,2×2H), 2.97 (t, 2H), 2.19 (tt, 2H), 1.49 (s, 9H), 1.38 (t, 3H).

e) Ethyl9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate

Ethyl9-(3-tert-butoxycarbonylamino-prop-1-ynyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate(318 mg, 0.77 mmol) was dissolved in dichloromethane (50 mL), treatedwith 10% palladiun on carbon (200 mg) and hydrogenated at roomtemperature and atmospheric pressure overnight. The reaction mixture wasfiltered and concentrated to provide a brown oil which was purified bychromatography on silica gel eluting with 0-1% (9:1 MeOH/20 M NH₃) indichloromethane to yield the title compound as a brown oil. ESMS m/z 415(MH⁺). ¹H NMR (CDCl₃) δ 8.34 (s, 1H), 8.11 (bs, 1H), 7.25 (bs, 1H), 4.60(m, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.13 (q, 2H), 3.02 (t, 2H), 2.71(t,2H), 2.20 (tt, 2H), 1.85 (tt, 2H), 1.44 (s, 9H), 1.40 (t, 3H).

f)9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid sodium salt

Ethyl9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate(240 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL) and treatedwith 2N aqueous sodium hydroxide (0.32 mL). The solution was heated to50° C. overnight then treated with excess solid carbon dioxide.Evaporation of the solvent gave the title compound as a beige solid.ESMS m/z 387 (MH⁺). NMR (DMSO-d₆) δ 8.83 (s, 1H), 8.11 (bs, 1H), 7.99(s, 1H), 7.57 (s, 1H), 6.89 (bt, 1H), 4.41 (bt, 2H), 3.04 (t, 2H), 2.94(q, 2H), 2.71 (t,2H), 2.13 (m, 2H), 1.74 (m, 2H), 1.37 (s, 9H).

g)9-(3-Amino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid trifluoroacetate salt

9-(3-tert-Butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylicacid sodium salt (224 mg, 0.58 mmol) was dissolved in trifluoroaceticacid (3 mL). After 0.5 h at room temperature the reaction mixture wasconcentrated to provide the title compound as a beige solid. ESMS m/z287 (MH⁺). NMR (MeOD-d₄) δ 8.83 (s, 1H), 8.15 (d, 1H), 7.62 (d, 1H),4.43 (t, 2H), 3.14 (t, 2H), 2.98 (t, 2H), 2.89 (t, 2H), 2.66 (tt, 2H),2.05 (tt, 2H).

Intermediate 13:4″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

The title compound was prepared from Intermediate 3 by the proceduredescribed below (see Table following Example 26).

Intermediate 14: 4″-O-Allyl-2′-O-acetylazithromycin-11,12-cycliccarbonate

To a solution of 2′-O-acetyl azithromycin-11,12-carbonate (0.408 g, 0.5mmoL) in dry THF (4 mL) under an atmosphere of nitrogen, was addedtetrakistriphenylphosphine palladium (0.057 g, 0.05 mmol) and allylt-butyl carbonate (0.30 g, 1.9 mmoL). The resulting mixture was stirredunder reflux. After 18 h of reflux TLC indicated 50% conversion of thedesired product. The solvent was evaporated and the crude productdissolved in 4 mL of methanol. The mixture was stirred overnight at roomtemperature and then concentrated under reduced pressure. The crudeproduct was purified by flash chromatography over silica gel elutingwith 90:9:0.5; dichloromethane/MeOH/aq. NH₃ to yield 0.24 g (56%) of apale yellow crystals. MS (m/z) 815 (MH⁺).

Intermediate 15: 4″-(2-Oxo-ethoxy)-azithromycin 11,12-cyclic carbonate

To a solution of Intermediate 14 (0.20 g, 0.23 mmoL) in THF (1 mL) andwater 1 mL), was added osmium tetraoxide (2.0 mL of a 2.5% solution inTHF). After stirring for 5 minutes, sodium periodate (0.213 g, 1 mmoL)was added in one portion. The mixture was vigorously stirred for 12 h at25° C. before being quenched with saturated aqueous Na₂SO₃ (10 mL). Theresulting solution was stirred at 25° C. for 2 h and then partitionedbetween EtOAc (22 mL) and water (5.0 mL). The organic phase wasseparated and the aqueous phase was extracted with EtOAc (2×10 mL). Thecombined organic extracts were dried (K₂CO₃) and the solvents wereremoved under reduced pressure. Flash column chromatography (silica gel,90:9:0.5; dichloromethane/MeOH/aq. NH₃) provided the correspondingaldehyde as a bright yellow solid (ca. 160 mg; 81% yield). MS (m/z) 817(MH⁺).

Intermediate 16: 4″-(3-Carboxy-propoxy)-azithromycin a)4″-(3-Methoxycarbonyl-allyloxy)-azithromycin 11,12-cyclic carbonate

A mixture of Intermediate 15 (587.6 mg, 0.719 mmoL) andmethoxycarbonylmethylene triphenyl phosphorane (360 mg, 1.08 mmoL, 1.5mol equiv.) in benzene (7.2 mL) was heated at reflux for 18 h. Aftercooling to 25° C. the solvent was removed under reduced pressure. Flashcolumn chromatography (silica gel, 90:9:0.5 CH₂Cl₂:MeOH:aq. NH₃)furnished unsaturated methyl ester 313.8 mg, 50%) as a mixture of Z andE isomers in 1:1 ratio according LC/MS analysis. MS (m/z) 873 (MH⁺).

b) 4″-(3-Methoxycarbonyl-propoxy)-azithromycin 11,12-cyclic carbonate

The mixture of Intermediate 16a from above (200 mg, 0.23 mmoL) wasdissolved in MeOH (5 mL), treated with Pd/C (50 mg, 10 wt % Pd) andcatalytically hydrogenated in Parr apparatus for 5 h. After filtrationthrough a Celite pad, the filtrate was concentrated in vacuo and theresidue purified by column chromatography (eluting with 90:9:0.5;dichloromethane/MeOH/aq. NH₃) to give 125 mg (62%) of pure ester as acolourless crystalline solid. MS (m/z) 875 (MH⁺).

c) 4″-(3-Carboxy-propoxy)-azithromycin

To a solution of Intermediate 16b (875 mg, 1.0 mmoL) in 1:1 THF-water(10.0 mL) at room temperature, was added LiOH (192 mg, 4.57 mmoL), andthe resulting reaction mixture was stirred at the same temperature for12 h. The solvent was removed under reduced pressure, and the solid wasazeotroped with benzene (5 mL×5) and finally dried under vacuum. Theacid salt was dissolved in water and the resulting solution was madeacidic by dropwise addition of 2M aqueous HCl. The precipitate wasfiltered of to give 787 mg (90%) of pure title compound. MS (m/z) 835(MH⁺).

Intermediate 17:1-Ethyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acida)6-(4-tert-Butoxycarbonyl-piperezin-1-yl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

An oven-dried Pyrex flask was charged with sodium tert-butoxide (134.5mg, 1.4 mmoL), Pd₂(dba)₃ (2.3-9.2 mg, 0.0025-0.01 mmoL) and BINAP(4.7-18.7 mg, 0.0075-0.03 mmoL). The Pyrex tube was fitted with aseptum, and the air atmosphere was replaced with argon, dry THF (2-9mL), 6-iodo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethylester (371.2 mg, 1.0 mmoL), and N-Boc-piperazine (223.5 mg, 1.2 mmoL)were added by syringe. The reaction was heated to 80° C. with stirringuntil the starting material was consumed as judged by LC-MS analysis.The reaction mixture was cooled to room temperature, diluted with ether(15 mL), filtered, and concentrated. The crude reaction mixture was thenpurified further by flash chromatography on silica gel to give 356.5 mg(83%) of the title compound as a pale yelow solid. MS (m/z) 430 (MH⁺).

b) 1-Ethyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester

A solution of Intermediate 17a (429.5 mg, 1.0 mmoL) in 10 mL of CH₂Cl₂and trifluoroacetic acid (1:1) was stirred at 0° C. for 5 hours. Thevolatile materials were evaporated under reduced pressure, and theresidue was triturated with diethylether and filtered. The resultingproduct (354.7 mg, 80%) was used without further purification in thenext step. MS (m/z) 330 (MH⁺).

c) 1-Ethyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid

Intermediate 17b was dissolved in a mixture of THF, water and 5 eq ofNaOH and stirred at 80° C. until TLC showed a complete conversion to thetitle compound. MS (m/z) 302 (MH⁺).

Example 14″-O-(2-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-erythromycinA 11,12-carbonate bis trifluoroacetate

a)2′-O,3′-N-bis(Benzyloxycarbonyl)-3′-N-desmethyl-6-O-methyl-erythromycinA

To a stirred mixture of 6-O-methyl-erythromycin A (20 g, 26.8 mmol) andsodium hydrogen carbonate (30 g) cooled in an ice bath was addedportionwise benzyl chloroformate (60 mL). After 10 min the ice bath wasremoved and the mixture was stirred for 15 min. The reaction was thenheated at 60-70° C. for 1 h. After cooling, the reaction mixture wasloaded onto a silica gel column (150 g) and eluted with a gradient of10-50% ethyl acetate in hexane. Evaporation of the product containingfractions gave the title product as a white solid foam (20.22 g); ESMSm/z 1024 [M+Na]⁺, 1060 [M+NH4+acetonitrile]⁺.

b)4″-O-Allyloxycarbonyl-2′-O,3′-N-bis(benzyloxycarbonyl)-3′-N-desmethyl-6-O-methyl-erythromycinA 11,12-carbonate

Example 1a (13 g, 12.97 mmol) in dichloromethane (50 mL) at 0° C. underargon was added pyridine (11.5 mL) and a solution of phosgene in toluene(20%, 30 mL). After 30 min the mixture was allowed to warm to 20° C.After 2.5 h the reaction was recooled to 0° C. and allyl alcohol (5 mL)was added dropwise. After stirring at 0° C. for 15 min and 20° C. for 30min the mixture was poured onto ice. Extraction with diethyl ether andwashing with water, 5% aq citric acid, and saturated aq sodium hydrogencarbonate gave a crude product solution which was dried, evaporated andpurified by chromatography (silica gel, 20-50% ethyl acetate in hexane)to give the title product as a white solid foam (12.5 g); ESMS m/z 1129[M+NH4]⁺, 1134 [M+Na]⁺, 1170 [M+NH4+acetonitrile]⁺.

c)4″-O-Allyl-2′-O,3′-N-bis(benzyloxycarbonyl)-3′-N-desmethyl-6-O-methyl-erythromycinA 11,12-carbonate

Example 1b (7.9 g, 7.1 mmol) in tetrahydrofuran (50 mL) was treated withtetrakis(triphenylphosphine)palladium (0.16 g). The reaction was heatedto reflux for 30 min after which time methyl allyl carbonate (1.7 mL)was added. After a further 1.75 h reflux, the reaction was cooled andevaporated to dryness. The residue was purified by chromatography(silica gel, 0-30% ethyl acetate in dichloromethane) to give the titleproduct as a white solid foam (3.93 g); ESMS m/z 1085 [M+NH4]⁺, 1090[M+Na]⁺, 1126 [M+NH4+acetonitrile]⁺.

d)2′-O,3′-N-bis(Benzyloxycarbonyl)-4″-O-{2-[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-6-O-methyl-3′-N-desmethyl-erythromycinA 11,12-carbonate

To Example 1c (0.256 g, 0.25 mmol) in tetrahydrofuran (1 mL) and water(1 mL) under argon was added osmium tetroxide (4% in water, 0.015 mL).After 5 min sodium periodate (0.213 g, 1 mmol) was added. After 2.5 hthe mixture was diluted with diethyl ether and water. The organic phasewas washed with saturated aq. sodium thiosulphate, dried, and evaporatedto dryness to give the crude aldehyde as a white solid foam (0.255 g).This material (0.094 g) in methanol (1.5 mL) and dimethylformamide (1.5mL) was treated with acetic acid (0.15 mL),7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (Yoshida et al, J. Pharm. Soc. Japan, 1990, 110, 258) (0.031 g, 0.1mmol) and sodium cyanoborohydride (0.013 g, 0.2 mmol). After 3 h thereaction was evaporated to dryness, and the residue purified bychromatography (silica gel, 0-10% 2 M methanolic ammonia indichloromethane) to give the title product as a white solid foam (0.066g); ESMS m/z 1359 [M+H]⁺.

e)4″-O-(2-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-erythromycinA 11,12-carbonate bistrifluoroacetate

Example 1d (0.066 g) in ethanol (20 mL) and dioxan (10 mL) washydrogenated at 50 psi over palladium hydroxide (20% on carbon, 0.080 g)for 72 h. The catalyst was removed by filtration, washed well withdioxan and ethanol, and the combined filtrates evaporated to dryness.The residue was taken up in ethanol (20 mL) and dioxan (10 mL), and 28%aq formaldehyde (2 mL), 0.7 min pH 4.5 acetate buffer (2 mL) andpalladium hydroxide (20% on carbon, 0.080 g) added. The mixture washydrogenated at 50 psi for a further 5 days, then the catalyst wasremoved by filtration, washed well with dioxan and ethanol, and thecombined filtrates evaporated to dryness. The residue was purified bychromatography (silica gel, 5-10% methanol in dichloromethane then10-20% 2 M methanolic ammonia in dichloromethane). Later fractionscontained impure title product. Early eluted fractions contained3′-N-benzyloxycarbonyl-4″-O-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-3′-N-desmethyl-erythromycinA 11,12-carbonate, (0.01 g) which was dissolved in ethanol (10 mL) anddioxan (5 mL) and hydrogenated at 50 psi over palladium (10% on carbon,0.1 g). After 3 h 28% aq. formaldehyde (1.5 mL), 0.7M pH 4.5 acetatebuffer (2.5 mL) was added and the hydrogenation continued for 24 h.After filtration and evaporation, the residue was purified bychromatography (silica gel, 2-15% 2M methanolic ammonia indichloromethane) giving impure product. Both batches of impure titleproduct were purified by preparative HPLC (acetonitrile/water/0.1%trifluoroacetic acid eluent) to give the title compound as a gum (0.004g); ESMS m/z 1119 [M+H]⁺.

Example 24″-O-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate

a)2′-O,3′-N-bis(Benzyloxycarbonyl)-4″-O-(3-hydroxypropyl)-3′-N-desmethyl-6-O-methyl-erythromycinA 11,12-carbonate

Example 1c (0.97 g, 0.908 mmol) in tetrahydrofuran (6 mL) was treatedwith 9-BBN (0.5M in tetrahydrofuran, 3.6 mL). After 1.5 h the reactionwas cooled to 0° C. and sodium hydroxide (2 M, 1.5 mL) and hydrogenperoxide (27% in water, 2.1 mL) were added. After 5 min the cooling bathwas removed and the reaction stirred for 15 m, then diluted with diethylether and water. The organic phase was washed with water and brine,dried (MgSO₄), and evaporated to dryness. The residue was purified bychromatography (silica gel, 0-50% ethyl acetate in dichloromethane) togive the title product as a white solid foam (0.80 g, 76%); ESMS m/z1103 [M+NH4]⁺, 1108 [M+Na]⁺.

b)2′-O,3′-N-bis(Benzyloxycarbonyl)-4″-O-{3-[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-propyl}]-6-O-methyl-3′-N-desmethyl-erythromycinA 11,12-carbonate trifluoroacetate

To Example 2a (0.411 g, 0.378 mmol) in dichloromethane (6 mL) at 0° C.under argon was added Dess-Martin periodinane (0.176 g, 0.41 mmol).After 1.5 h, the cooling bath was removed and the reaction stirred for afurther 30 min then diluted with dichloromethane, washed with saturatedaq sodium hydrogen carbonate, dried (MgSO₄), and evaporated to drynessto give the title product as a white solid foam (0.42 g). This material(0.169 g) in methanol (2 mL) and dimethylformamide (2 mL) was treatedwith acetic acid (0.2 mL),7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (0.048 g, 0.16 mmol) and sodium cyanoborohydride (0.02 g, 0.32mmol). After 1.5 h the reaction was evaporated to dryness, and theresidue purified by preparative HPLC (acetonitrile/water/0.1%trifluoroacetic acid eluent) to give the title product (0.10 g); ESMSm/z 1373 [M+H]⁺.

c)4″-O-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate

Example 2b (0.1 g) in ethanol (20 mL) and dioxan (10 mL) washydrogenated at 50 psi over palladium (10% on carbon, 0.050 g) for 7 h.28% aq. Formaldehyde (2.5 mL), 0.7 M pH 4.5 acetate buffer (5 mL) wasadded and the hydrogenation continued for 24 h. After filtration andevaporation, dichloromethane (10 mL) and methanol (2 mL) were added tothe residue and insoluble material removed by filtration. The solublematerial was passed down a silica gel column eluting with 2-15% 2 Mmethanolic ammonia in dichloromethane. The fractions containing thetitle material were dissolved in ethanol (10 mL), 28% aq. formaldehyde(1 mL) and 0.7 M pH 4.5 acetate buffer (2 mL) and the mixturehydrogenated at 50 psi over palladium (10% on carbon, 0.1 g) for 30 h.The catalyst was removed by filtration and the residue evaporated todryness. Dichloromethane (10 mL) and methanol (2 mL) were added to theresidue and insoluble material removed by filtration. The solublematerial was passed down a silica gel column eluting with 2-15% 2 Mmethanolic ammonia in dichloromethane to give the title product, as agum (0.012 g); ¹H NMR (CD₃OD) (inter alia) 1.8 (2H, m), 2.4 (3H, s), 2.6(2H, m), 2.8 (2H, m), 3.5 (2H, m), 3.7 (2H, m), 4.55 (1H, d), 4.65 (1H,s), 4.85 (1H, d), 5.0 (1H, dd), 7.2 (1H, d), 7.8 (1H, d), 8.7 (1H, s);ESMS m/z 1133 [M+H]⁺.

Example 34″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate bis trifluoroacetate

a) 4″-O-(3-Hydroxypropyl)-6-O-methyl-erythromycin A 11,12-carbonate

Example 2a (2.57 g, 2.37 mmol) in ethanol (25 mL) and dioxan (25 mL) washydrogenated at 50 psi over palladium (10% on carbon, 0.2 g) for 26 h.The catalyst was removed by filtration and the soluble material taken upin ethanol (50 mL), pH 4.5 buffer (4 mL) and 37% aq formaldehydesolution (4 mL) were added and the mixture hydrogenated at 50 psi overpalladium (10% on carbon, 0.5 g). After 18 h, the reaction mixture wasfiltered, and the catalyst washed well with ethanol and dioxan. Thecombined filtrates were purified by chromatography on silica gel elutingwith 0-10% 2 M methanolic ammonia in dichloromethane to give the titleproduct as a white foam (1.21 g); ESMS m/z 832 [M+H]⁺.

b)4″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate bis trifluoroacetate

To Example 3a (0.099 g, 0.119 mmol) in dichloromethane (2 mL) at 0° C.under argon was added Dess-Martin periodinane (0.176 g, 0.41 mmol).After 15 min the reaction was allowed to warm to 20° C. After a totalreaction time of 100 min the reaction mixture was diluted withdichloromethane, washed with saturated. aq sodium hydrogen carbonate,dried, and evaporated to dryness to give the crude aldehyde as a whitesolid foam. This material in DMF (1 mL) and methanol (1 mL) was treatedwith acetic acid (0.1 mL), Intermediate 2 (0.038 g, 0.12 mmol), sodiumacetate (0.01 g) and sodium cyanoborohydride (0.015 g, 0.24 mmol). After14 h the reaction was evaporated to dryness, and the residue partiallypurified by chromatography on silica gel eluting with 5-20% 2 Mmethanolic ammonia in dichloromethane followed by preparative HPLC(acetonitrile/water/0.1% trifluoroacetic acid eluent) to give the titleproduct (0.013 g); ESMS m/z 1090 [M+H]⁺.

Example 44″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate bisformate

To Example 3a (0.125 g, 0.119 mmol) in dichloromethane (2.5 mL) underargon was added Dess-Martin periodinane (0.095 g, 0.22 mmol). After 3.5h, the reaction mixture was diluted with dichloromethane, washed withsaturated aq sodium hydrogen carbonate, dried, and evaporated to drynessto give the crude aldehyde as a white solid foam. This, material wasdissolved in dimethylformamide (1.5 mL) and methanol (1.5 mL) andtreated with acetic acid (0.3 mL), Intermediate 3 (0.081 g, 0.2 mmol)sodium acetate (0.024 g) and sodium cyanoborohydride (0.015 g). After 3h the reaction was evaporated to dryness, and the residue purified bypreparative HPLC (acetonitrile/water/0.1% formic acid eluent) to givethe title product (0.024 g); ¹H NMR δ (CDCl₃) (inter alia) 1.6 (3H, t),2.0 (2H, m), 3.05 (2H, m), 3.65 (1H, m), 3.85 (1H, m), 4.4 (2H, q),4.55(1H, d), 4.6 (1H, s), 4.85 (1H, d), 5.0 (1H, dd), 7.65 (1H, d), 7.85(1H, d), 8.35 (2H, s), 8.4 (1H, s); ESMS m/z 1106 [M+H]⁺.

Example 54″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-erythromycinA bisformate

a) 4″-O-(1-imidazol-1-yl-carbonyl)-6-O-methyl-erythromycin A

6-O-Methyl-erythromycin A (30 g, 40.1 mmol) in tetrahydrofuran (100 mL)was treated portionwise with carbonyldiimidazole (16 g, 97 mmol) withice bath cooling. After 1 h the cooling bath was removed. After afurther 48 h, tetrahydrofuran (100 mL) and water (200 mL) were addedslowly precipitating the title compound, which was collected byfiltration and dried to give the title compound (24.7 g). Extraction ofthe mother liquors with diethyl ether gave further material (8.5 g)which was precipitated from tetrahydrofuran solution with water to givea further portion of the title compound (3.92 g, total of 28.64 g); ESMSm/z 842 [M+H]⁺.

b) 4″-O-(Allyloxycarbonyl)-6-O-methyl-erythromycin A

Example 5a (28.64 g, 34 mmol) in dichloromethane (100 mL) was cooled to0° C. and treated with allyl alcohol (13.6 mL) and DBU (5.23 mL). Thereaction was stirred at 0° C. for 2.5 h and at 20° C. for 1.75 h. Thereaction mixture was quenched with 3% aq citric acid (100 mL), thephases separated, and the organic phase washed with sat sodium hydrogencarbonate and brine. After drying and evaporation to dryness, theresidue was triturated with petroleum ether (bp 40-60° C.) to give thetitle compound as a solid (25.08 g); ESMS m/z 832 [M+H]⁺.

c)4″-O-(Allyloxycarbonyl)-9-dihydro-9-methoxy-2′,11-bis-O-trimethylsilyl-6-O-methyl-9,12-anhydro-erythromycinA

Example 5b (22.29 g, 25.6 mmol) in pyridine (100 mL) was treated withchlorotrimethylsilane (26 mL). The reaction was stirred at 20° C. for 6h and left at 4° C. for 16 h. The reaction mixture was evaporated todryness under reduced pressure and the residue taken up in methanol (100mL) After 80 min at 20° C., the solvent was removed by evaporation underreduced pressure and the residue taken up in ethyl acetate and water thephases were separated, the organic layer dried, and evaporated todryness under reduced pressure. Toluene (two 500 mL portions) were addedand evaporated under reduced pressure to give the crude title compoundas a white foam (26.27 g). This material (5.8 g) was purified bychromatography on silica gel eluting with 0-3% 2 M methanolic ammonia indichloromethane to give the title compound as a white foam (3.0 g); ESMSm/z 990 [M+H]⁺.

d)4″-O-Allyl-9-dihydro-9-methoxy-2′,11-bis-O-trimethylsilyl-6-O-methyl-9,12-anhydro-erythromycinA

Example 5c (3.0 g, 3.03 mmol) in tetrahydrofuran (20 mL) was treatedwith tetrakis triphenylphosphine palladium (0.1 g) at reflux underargon. After 35 min, t-butyl allyl carbonate (F. Houlihan et al, Can. J.Chem, 1985, 63, 153; 1.2 mL) and tetrakis(triphenylphosphine)palladium(0.1 g) were added and the reflux continued for a further 1 h. Thereaction was cooled and evaporated to dryness under reduced pressure,and the residue purified by chromatography on silica gel eluting with0-5% 2 M methanolic ammonia in dichloromethane to give the titleproduct, 1.07 g, as a white foam; ESMS m/z 946 [M+H]⁺.

e)9-Dihydro-4″-O-(3-hydroxypropyl)-9-methoxy2′,11-bis-O-trimethylsilyl-6-O-methyl-9,12-anhydro-erythromycinA

Example 5d (0.255 g, 0.27 mmol) in tetrahydrofuran (4 mL) under argonwas treated with 9-BBN (0.5 M in tetrahydrofuran, 1.6 mL). After 30 min,the reaction was cooled to 0° C. and a precooled mixture of sodiumhydroxide (2 M, 0.5 mL) and hydrogen peroxide (27% in water, 0.68 mL)were added. This was stirred at 0° C. for 10 min before addition of colddiethyl ether and water. The phases were separated and the organic phasewashed with water and brine. After drying and evaporation under reducedpressure the residue was purified by chromatography on silica geleluting with 0-10% 2 M methanolic ammonia in dichloromethane to give thetitle product as a White foam (0.16 g); ESMS m/z 964 [M+H]⁺.

f)4″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-erythromycinA bisformate

To Example 5e (0.16 g, 0.166 mmol) in dichloromethane (5 mL) under argonwas added Dess-Martin periodinane (0.085 g, 0.2 mmol). After 1 h, thereaction mixture was diluted with dichloromethane, washed with sat. aqsodium hydrogen carbonate, dried, and evaporated to dryness to give thecrude aldehyde as a gum. This material was dissolved in methanol (2.5mL) and dichloromethane (2.5 mL) and treated with acetic acid (0.25 mL),sodium acetate (0.028 g), 3A molecular sieves (0.3 g), Intermediate 4(0.0625 g, 0.16 mmol) and sodium cyanoborohydride (0.030 g). After 2 hthe reaction was evaporated to dryness, and toluene (5 mL) added andevaporated. The residue was purified by preparative HPLC(acetonitrile/water/0/1% formic acid eluent) and the fractions allowedto stand at 20° C. for 1 h which resulted in loss of protection. Afurther preparative HPLC (acetonitrile/water/0.1% formic acid eluent)purification gave the fitle product (0.034 g); ESMS m/z 1062 [M+H]⁺.

Example 64″-O-{3-[2-(2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate bisformate

To Example 3a (0.25 g, 0.33 mmol) in dichloromethane (5 mL) under argonwas added Dess-Martin periodinane (0.14 g, 0.33 mmol). After 2 h, moreDess-Martin periodinane (0.03 g) was added and the reaction stirred fora further 1.5 h. The reaction mixture was diluted with dichloromethane,washed with saturated. aq sodium hydrogen carbonate, dried, andevaporated to dryness to give the crude aldehyde as a white solid foam.This material (0.042 g, 0.05 mmol) in methanol/DCM (1:1, 2 mL) was addedto sodium acetate (0.008 g, 0.1 mmol), acetic acid (0.1 mL),Intermediate 5 (0.02 g, 80% pure, 0.05 mmol), and 3A molecular sieves(0.1 g). The mixture was stirred for 15 min then a solution of sodiumcyanoborohydride (0.0063 g, 0.1 mmol) in methanol (0.2 mL) was added andstirring continued for 3 h. The reaction was then filtered, washing wellwith methanol, and the filtrate evaporated. The residue was purified bypreparative reverse phase HPLC (MeCN/H2O/0.1% HCO2H eluent) to give thetitle compound as a pale yellow solid (0.031 g); ESMS m/z 1102 [M+H]⁺.

Example 74″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate formate

a)2′-O-Acetyl-4″-O-allyl-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate

Intermediate 7 (0.315 g, 0.38 mmol), t-butyl allyl carbonate (0.079 g,0.5 mmol) and tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol)in THF (10 mL) were refluxed for 4 h. More t-butyl allyl carbonate(0.079 g, 0.5 mmol) was added and refluxing continued for a further 2 h.More t-butyl allyl carbonate (0.04 g, 0.25 mmol) was added and refluxingcontinued for a further 1.5 h. The mixture was then evaporated todryness and the residue purified by chromatography on silica gel (40 g).Elutton with 0-4.5% 2 M methanolic ammonia in dichloromethane, gave thetitle compound (0.294 g); ESMS m/z 869 [M+H]⁺.

b) 4″-O-Allyl-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycin A11,12-carbamate

Example 7a (0.27 g, 0.31 mmol) in methanol (10 mL) was heated at 60° C.for 8.5 h, 45° C. for 15 h, and 60° C. for 3 h. The mixture was thenevaporated to dryness to give the title compound as a white solid (0.244g); ESMS m/z 827 [M+H]⁺.

c)2′-O,3′-N-bis(Benzyloxycarbonyl)-3′-N-desmethyl-4″-O-allyl-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate

Example 7b (0.24 g, 0.29 mmol) and sodium hydrogen carbonate (0.4 g) inbenzyl chloroformate (2 mL) were heated at 60° C. for 3 h. After coolingthe mixture was purified by chromatography on silica gel (50 g). Elutionwith 0-50% ethyl acetate in petroleum ether gave the title compound as awhite solid (0.272 g); ESMS m/z 1098 [M+NH₄]⁺.

d)2′-O,3′-N-bis(Benzyloxycarbonyl)-3′-N-desmethyl-4″-O-(3-hydroxypropyl)-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate

Example 7c (0.27 g, 0.25 mmol) in THF (8 mL) was treated with9-borabicyclo[3.3.1]nonane (0.5 M in THF, 1.5 mL, 0.75 mmol). After 4 hmore 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 0.5 mL, 0.25 mmol) wasadded. Further 1 h then more 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 1mL, 0.5 mmol) was added. After 1 h more the solution was cooled in anice bath then pre-mixed hydrogen peroxide (30% aq, 1.7 mL, 15 mmol) insodium hydroxide (2 N, 2.5 mL, 5 mmol) was added. The cooling bath wasremoved and the mixture stirred for 0.5 h. The reaction was diluted withwater and extracted with ethyl acetate (×3). The combined organicextracts were washed with brine, dried, and evaporated to give the crudeproduct. This was purified by chromatography on silica gel (40 g),eluting with 30-80% ethyl acetate in petroleum ether, to give the titlecompound as a white solid (0.139 g); ESMS m/z 1116 [M+NH₄]⁺.

e)4″-O-(3-Hydroxypropyl)-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate

Example 7d (0.137 g, 0.125 mmol) was dissolved in ethanol (4 mL) and1,4-dioxane (6 mL), and hydrogenated over 10% palladium on charcoal (50%aq paste,0.06 g) for 6.5 h. Formaldehyde (37% aq, 0.3 mL), pH 4.5acetate buffer (0.3 mL) and more catalyst (0.05 g) were then added, andthe mixture hydrogenated for 16 h. The mixture was then filtered,washing well with ethanol and 1,4-dioxane. The filtrate was evaporated,and the residue purified by chromatography on silica gel (5 g). Elutionwith 0-6% 2 M methanolic ammonia in dichloromethane, gave the titlecompound as a white foam (0.083 g); ESMS m/z 845 [M+H]⁺.

f)4″-O-(3-Oxopropyl)-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate

To Example 7e (0.082 g, 0.097 mmol) in DCM (3 mL) was added Dess-Martinperiodinane (0.047 g, 0.11 mmol). The reaction was stirred for 1.75 h,then more oxidant (0.018 g) added. After a further 1.5 h, the reactionwas diluted with DCM, washed with aq sodium hydrogen carbonate, driedand evaporated to give the crude title compound as a white foam (0.086g), which was used without purification; ESMS m/z 843 [M+H]⁺.

g)4″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycinA 11,12-carbamate formate

Example 7f (0.082 g, 0.097 mmol) in methanol/DCM (1:1, 4 mL) was addedto sodium acetate (0.0164 g, 0.2 mmol), acetic acid (0.2 mL),Intermediate 4 (0.0274 g, 0.1 mmol), and 3A molecular sieves (0.2 g).The mixture was stirred for 20 min then a solution of sodiumcyanoborohydride (0.0126 g, 0.2 mmol) in methanol (0.3 mL) was added andstirring continued for 16 h. The reaction was then filtered, washingwell with methanol and DCM, and the filtrate evaporated. The residue waspurified by preparative reverse phase HPLC (MeCN/H₂O/0.1% HCO₂H eluent)to give the title compound as an off-white powder (0.038 g, 35%); ESMSm/z 1101 [M+H]⁺.

Example 84″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

a)2′-O,3′-N-bis(Benzyloxycarbonyl)-3′-N-desmethyl-4″-O-[3-(tert-butyldimethylsilyl-oxy)propyl]-6-O-methyl-erythromycinA 11,12-carbonate

Example 2a (1.85 g, 1.71 mmol) in DMF (10 mL) was treated sequentiallywith imidazole (0.128 g, 1.88 mmol) and tert-butyldimethylsilyl chloride(0.283 g, 1.88 mmol). Mixture stirred for 20 h then evaporated. Waterwas added and the mixture extracted with diethyl ether. The combinedorganic extracts were washed with brine, dried, and evaporated. Theresidue was purified by chromatography on silica gel (100 g), elutingwith 12-42% ethyl acetate in petroleum ether, to give the title compoundas a white foam (1.923 g); ESMS m/z 1217 [M+NH₄]⁺.

b)2′-O,3′-N-bis(Benzyloxycarbonyl)-3′-N-desmethyl-4″-O-[3-(tert-butyldimethylsilyl-oxy)propyl]-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate

Example 8a (1.9 g, 1.58 mmol), carbonyldiimidazole (1.28 g, 7.2 mmol),imidazole (0.01 g) and DBU (0.08 g, 0.52 mmol) were dissolved in THF (10mL), heated to 40° C. and stirred for 17 h. Further portions ofcarbonyldiimidazole and DBU were added, and reaction heated at 60° C.for 6 h then 50° C. for 16 h. The mixture was then cooled in an ice bathand ammonia gas bubbled in for 8 h. The reaction was then stored in thefridge for 14 h. Argon was then bubbled through the mixture before theaddition of potassium tert-butoxide (1 M in THF, 1.74 mL, 1.74 mmol).After 5 h at room temperature more potassium tert-butoxide (1 M in THF,1 mL, 1 mmol) was added. Further 2 h then more potassium tert-butoxide(1 M in THF, 0.5 mL, 0.5 mmol) added. The mixture was then stirred for64 h. Aqueous sodium hydrogen carbonate was then added and the mixtureextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried, and evaporated. The residue was purified bychromatography on silica gel (100 g), eluting with 20-52% ethyl acetatein petroleum ether, to give the title compound as a white foam (1.3 g);ESMS m/z 1216 [M+NH₄]⁺.

c)4″-O-[3-(tert-butyldimethylsilyl-oxy)propyl]-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate

Example 8b (1.4 g, 1.17 mmol) was dissolved in methanol (10 mL) and1,4-dioxane (15 mL), and hydrogenated over 10% palladium on charcoal(50% aq paste, 0.4 g) for 6 h. Formaldehyde (37% aq, 4 mL), pH 4.5acetate buffer (4 mL) and more catalyst (0.2 g) were then added, and themixture, hydrogenated for 24 h. The mixture was then filtered, washingwell with methanol and 1,4-dioxane. The filtrate was evaporated, and theresidue purified by chromatography on silica gel (100 g). Elution with0-7% 2 M methanolic ammonia in dichloromethane, gave the title compoundas a white foam (0.969 g); ESMS m/z 945 [M+H]⁺.

d) 4″-O-(3-Hydroxypropyl)-6-O-methyl-11-desoxy-11-(R)-aminoerythromycinA 11,12-carbamate

Example 8c (0.17 g, 0.18 mmol) in THF (4 mL) and acetic acid (0.023 mL,0.4 mmol) was treated with tetrabutylammonium fluoride (1 M in THF, 0.4mL, 0.4 mmol). The mixture was stirred at 35° C. for 72 h, thenevaporated to dryness, and the residue purified by chromatography onsilica gel (40 g). Elution with 0-11% 2 M methanolic ammonia indichloromethane, gave the title compound as a white foam (0.15 g); ESMSm/z 831 [M+H]⁺.

e) 4″-O-(3-Oxopropyl)-6-O-methyl-11-desoxy-11-(R)-aminoerythromycin A11,12-carbamate

To Example 8d (0.085 g, 0.1 mmol) in DCM (2 mL) was added Dess-Martinperiodinane (0.051 g, 0.12 mmol) in DCM (1 mL). Stirred for 1.3 h, thendiluted with DCM, washed with aq sodium hydrogen carbonate, dried andevaporated to give the crude title compound as a white foam (0.097 g),which was used without purification; ESMS m/z 829 [M+H]⁺.

f)4″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 8e (0.082 g, 0.1 mmol) in methanol/DCM (1:1, 4 mL) was added tosodium acetate (0.025 g, 0.3 mmol), acetic acid (0.2 mL), Intermediate 4(0.043 g, 0.11 mmol), and 3A molecular sieves (0.2 g). The mixture wasstirred for 30 min then a solution of sodium cyanoborohydride (0.0126 g,0.2 mmol) in methanol (0.3 mL) was added and stirring continued for 2.5h. The reaction was then filtered, washing well with methanol and DCM,and the filtrate evaporated. The residue was purified by preparativereverse phase HPLC (MeCN/H₂O/0.1% HCO₂H eluent) to give the titlecompound as a pale yellow solid (0.054 g, 46%); ESMS m/z 1087 [M+H]⁺.

Example 94″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate formate

Example 104″-O-{3-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate formate

Example 114″-O-{3-[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate formate

Example 124″-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate formate

To 4″-O-(3-hydroxypropyl)-6-O-methylerythromycin A 11,12-carbonate(0.883 g, 1.06 mmol) in dichloromethane (20 mL) under argon was addedDess-Martin periodinane (0.495 g, 1.17 mmol). After 3 h, moreDess-Martin periodinane (0.1 g, 0.24 mmol) was added, and after 1.5 hmore Dess-Martin periodinane (0.11 g, 0.26 mmol) was added. The mixturewas stirred for a further 35 min then diluted with dichloromethane,washed with saturated aqueous sodium hydrogen carbonate, dried,filtered, and concentrated in vacuo to give the crude aldehyde as awhite solid foam. This material was dissolved in methanol (20 mL) anddichloromethane (20 mL), then split into four equal portions which wereused in the general procedure for reductive amination.

General Procedure for Reductive Amination

To the solution of aldehyde in methanol (5 mL) and dichloromethane (5mL) was added sodium acetate (0.044 g, 0.54 mmol), acetic acid (0.5 mL),3A molecular sieves (0.5 g), and the amine (0.26 mmol). The mixture wasstirred for 10 min then a solution of sodium cyanoborohydride (0.033 g,0.5 mmol) in methanol (0.5 mL) was added and stirring continued for 20h. The reaction was then filtered through Celite, and concentrated invacuo to give a residue which was purified by preparative reverse phaseHPLC (MeCN/H₂O/0.1% HCO₂H eluent), then further purified bychromatography (silica gel, 0-20% 2 M methanolic ammonia indichloromethane) to give the title compound. Product Example mass ESMSm/z Amine intermediate no. (g) [M + H]⁺ 4 9 0.096 1088 1 10 0.111 11357-(2-aminoethylamino)-1- 11 0.103 1119 cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 6 12 0.084 1108

Example 134″-O-(3-{[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate formate

Example 144″-O-(3-{[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate

Example 154″-O-(3-{[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8naphthyridin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate

General Procedure for N-Methylation

To a solution of amine starting material (0.072 mmol) as tabulated belowin chloroform (2 mL) was added formic acid (0.005 mL, 0.144 mmol), andformaldehyde (37% by weight in water) (0.011 mL, 0.144 mmol). Themixture was heated to 60° C. for 3 h then concentrated in vacuo to givea residue which was purified by chromatography (silica gel, 0-20% 2 Mmethanolic ammonia in dichloromethane) or by preparative reverse phaseHPLC (MeCN/H₂O/0.1% HCO₂H eluent) to give the title compound. ESMS m/zStarting material Example no. [M + H]⁺ Example 9 13 1102 Example 10 141149 Example 12 15 1122

Example 164″-O-{2-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propylamino]ethyl}azithromycin11,12-carbonate

a) 2′-O-Acetyl-azithromycin 11,12-carbonate

To a suspension of azithromycin 11,12-carbonate (B. A. Jones et al.,Tet. Lett., 1993, 34, 4913; 100 g, 0.13 mol) and sodium hydrogencarbonate (44 g, 0.52 mol) in dichloromethane (400 mL) was addeddropwise acetic anhydride (20.4 mL, 0.2 mol). After stirring overnightthe mixture was diluted with water (400 mL) and the organic layerseparated, dried and evaporated to yield the title compound as a whitesolid; ESMS m/z 818 (MH⁺).

b) 2′-O-Acetyl-4″-O-allyl-azithromycin 11,12-carbonate

To a solution of Example 16a (0.408 g, 0.5 mmol) in dry THF (4 mL) andtetrakis(triphenyphosphine)palladium (0.057 mg, 0.05 mmol) was addedallyl t-butyl carbonate (0.300 g, 1.89 mmol). After heating at refluxunder argon for 8 h the mixture was cooled and the solvent evaporated.Chromatography of the residue over silica gel eluting withdichloromethane containing an increasing concentration of methanol(0-1%) gave the title compound as a pale yellow gum; ESMS m/z 857 (MH⁺).

c) 2′-O-Acetyl-4″-O-(2-oxoethoxy)azithromycin 11,12-carbonate

To a cooled solution of Example 16b (0.20 g, 0.23 mmol) in THF (1 mL)and water (1 mL) was added osmium tetraoxide (15 μL of a 4% solution inwater). After 5 mins solid sodium periodate (0.21 g, 1 mmol) was addedin one portion and the resultant mixture stirred at room temperature for4 h. Sodium hydrogen sulfite (0.19 g, 1 mmol) was added and the organicmaterial extracted with ethyl acetate (2×15 mL). The combined organicfractions were dried and evaporated to yield the title compound as abrown gum; ESMS m/z 877 (MNH₄ ⁺).

d)4″-O-{2-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propylamino]ethyl}azithromycin11,12-carbonate

A solution of Example 16c (0.054 g, 0.063 mmol), Intermediate 4 (0.05 g,0.127 mmol) and sodium acetate (0.011 g, 0.127 mmol) in 1% aceticacid/methanol (2 mL) was stirred for 0.5 h at room temperature. Sodiumcyanoborohydride (0.016 mg, 0.25 mmol) was added. After 16 h the mixturewas concentrated and purified by reverse phase liquid chromatography toyield the title compound as a white solid; ESMS m/z 1076 (MH⁺).

Example 174″-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)ethylamino]ethyl}azithromycintris trifluoroacetate

a)2′-O-Acetyl-4″-O-{2-[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)ethylamino]ethyl}azithromycin11,12-carbonate

Using a similar procedure to that described in Example 16d, Example 16c(0.055 g, 0.063 mmol) and Intermediate 3 (0.030 g, 0.95 mmol) gave thetitle compound as a white solid; ESMS m/z 1136 (MH⁺).

b)4″-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)ethylamino]ethyl}azithromycintris trifluoroacetate

A solution of Example 17a in methanol (2 mL) containing sodium hydrogencarbonate (0.010 g, 0.12 mmol) was stirred at 50° C. After 4 h themixture was cooled, filtered and the solvent evaporated to yield thecrude product. Purification by reverse phase liquid chromatography gavethe title compound as a colorless gum; ESMS m/z 1094 (MH⁺).

Example 184″-O-{2-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-amino}-ethyl}-6-O-methyl-erythromycinA monoformate

a)9-Dihydro-9-methoxy-4″-O-2-oxoethyl-2′,11-bis-O-trimethylsilyl-6-O-methyl-9,12-anhydro-erythromycinA

To Example 5d (0.6 g, 0.64 mmol) in THF (2.5 mL) and water (2.5 mL)under argon was added osmium tetroxide (4% solution in water, 0.04 mL).After 5 min sodium periodate (0.535 g, 2.5 mmol) was added. Afterstirring for 4.5 h, the reaction was diluted with ethyl acetate (20 mL)and washed with sat. aq. sodium thiosulfate (5 mL) and brine (5 mL).After drying with magnesium sulfate, the solution was evaporated to givethe title material as a white foam, (0.62 g); ESMS m/z 966 [M+H₂O+H]⁺.

b)4″-O-{2-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-amino}-ethyl}-6-O-methyl-erythromycinA monoformate

To Example 18a (0.1 g, 0.1 mmol) in methanol/DCM (1:1, 3 mL) was addedto sodium acetate (0.025 g, 0.3 mmol), acetic acid (0.15 mL),Intermediate 6 (0.041 g, 0.01 mmol), and 3A molecular sieves (0.2 g).The mixture was stirred for 45 min then a solution of sodiumcyanoborohydride (0.0128 g, 0.2 mmol) in methanol (0.8 mL) was added andstirring continued for 3 h. The reaction was then filtered, washing wellwith methanol, and the combined filtrates evaporated. The residue wasdissolved in acetonitrile (20 mL), and 1% aq. Formic acid (15 mL) for 10min at 20° C. before evaporation to dryness. The crude product waspurified by preparative reverse phase HPLC (MeCN/H2O/0.1% HCO2H eluent)to give the title compound as a yellow foam (0.037 g); ESMS m/z 1068[M+H]⁺.

Example 194″-O-{2-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-ethyl}-6-O-methyl-erythromycinA

To a solution of Example 18 (0.033 g) in chloroform (1 mL) was addedformic acid (0.005 mL, 0.144 mmol), and formaldehyde (37% by weight inwater) (0.005 mL, 0.144 mmol). The mixture was heated to 60° C. for 3 hwhen further 0.005 mL portions of the reagents were added. After afurther 1.5 h heating the reaction mixture was concentrated in vacuo togive a residue which was purified by preparative reverse phase HPLC(MeCN/H₂O/0.1% HCO₂H eluent) to give the title compound, (0.016 g). ESMSm/z 1082 [M+H]⁺.

Example 204″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propoxy]-propyl}-6-O-methyl-erythromycinA monoformate

a)4″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propoxy]-prop-1-enyl}-6-O-methyl-erythromycinA ethyl ester

To Example 5e (0.12 g, 0.125 mmol) and Intermediate 8 (0.1 g) in THF (2mL) under argon was added tetrakis(triphenylphosphine)palladium (0.007g). The reaction was heated to reflux for 15 min after which furtherIntermediate 8 (0.1 g) and tetrakis(triphenylphosphine)palladium (0.007g) were added. After a further 40 min reflux, further Intermediate 8(0.075 g) and tetrakis(triphenylphosphine)palladium (0.007 g) wereadded. The reaction was refluxed for a further 35 min cooled andevaporated to dryness. The residue was taken up in acetonitrile/0.2M aq.formic acid (50 mL, 50:50) and left at 20° C. for 20 h. Afterevaporation to dryness, the residue was purified chromatography oversilica gel eluting with 0-10% 2M methanolic ammonia in dichloromethaneto yield the title compound as a gum (0.175 g); ESMS m/z 1089 [M+H]⁺.

b)4″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propoxy]-propyl}-6-O-methyl-erythromycinA ethyl ester

Example 20a (0.175 g), in ethanol was hydrogenated at 20° C. and 1 atmover 10% Pd/C (0.05 g) for 3 h. The reaction was filtered, and thefiltrate evaporated to give the title product, (0.175 g) as a gum, ESMSm/z 1091 [M+H]⁺.

c)4″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propoxy]-propyl}-6-O-methyl-erythromycinA

Example 20b (0.175 g), in 1,4dioxan (5 mL) under argon was treated withwater (1 mL) containing lithium hydroxide (0.012 g). After stirring for75 min, the reaction mixture was evaporated to low volume, and theresidue taken up in water and solid CO₂ added. After evaporation todryness, the residue was purified by preparative reverse phase HPLC(MeCN/H₂O/0.1% HCO₂H eluent) to give the fitle compound, (0.036 g) ESMSm/z 1063 [M+H]⁺.

Example 214″-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 224″-O-{3-[2-(2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yloxy)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 234″-O-{3-[3-(3-Carboxy-1-ethyl-5-methyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 244″-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-6-[1,8]naphthryidinyl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 254″-O-{3-[3-(2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)-propylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 264″-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-4-H-quinolizin-7-ylamino)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Using the method of Example 8f the amino acids tabulated below wereconverted to the title compounds. Purification was by chromatography(silica gel, 0-20% 2 M methanolic ammonia in dichloromethane) and/or bypreparative reverse phase HPLC (MeCN/H₂O/0.1% HCO₂H eluent) asappropriate. ESMS m/z Intermediate Example no. [M + H]⁺ 6 21 1107 5 221101 9 23 1101 11 24 1088 12 25 1099 3 Intermediate 13 1105 10 26 1088

Example 274″-O-{3-[[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 284″-O-{3-[[2-(2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yloxy)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 294″-O-{3-[[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate formate

Example 304″-O-{3-[[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-6-[1,8]naphthryidinyl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate

Example 314″-O-{3-[[3-(2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate

Example 324″-O-{3-[[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate

To a solution of starting material as tabulated below in chloroform (30mL/mmol) was added formic acid (4 equivalents), and formaldehyde (37% byweight in water) (2 equivalents). The mixture was heated to 60° C. for 3h then concentrated in vacuo to give a residue which was purified bychromatography (silica gel, 0-20% 2 M methanolic ammonia indichloromethane) and/or by preparative reverse phase HPLC (MeCN/H₂O/0.1%HCO₂H eluent) to give the title compound. ESMS m/z Starting materialExample no. [M + H]⁺ Example 21 27 1121 Example 22 28 1115 Example 8 291101 Example 24 30 1102 Example 25 31 1113 Intermediate 13 32 1119

Example 334″-O-{3-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylcarbamoyl]-propyl}-azithromycin

DIPEA (201.4 μL, 1.4 mol. equiv.) was added dropwise via a syringe at 0°C. to a solution of Intermediate 16c (181.7 mg, 0.22 mmoL) and HBTU(81.7 mg, 0.22 mmoL) in dry DMF (2.6 mL). The mixture was stirred for 15minutes before7-(2-amino-ethylamino)-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (48.7 mg, 0.16 mmoL) was added over a period of 30 minutes. Thereaction mixture was stirred at room temperature overnight, and thendiluted with water (30 mL). The aqueous phase was extracted twice withEtOAc (2×50 mL), and the combined organic phases were washedsequentially with saturated aqueous NaHCO₃ (30 mL) and brine (30 mL).Drying with Na₂SO₄ and evaporation afforded 127.5 mg (71%) of the titlecompound as a colourless solid. MS (m/z) 1122 (MH⁺).

Example 344″-O-{3-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylcarbamoyl]-propyl}-azithromycin

Starting from Intermediate 16c (834 mg, 1.0 mmoL) and Intermediate 1(234.9 mg, 0.73 mmoL) using a similar procedure to that described inExample 33, the title compound (620.5 mg) was obtained. MS (m/z) 1138(MH⁺).

Example 354″-O-{4-[4-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-yl)-piperazin-1-yl]-4-oxo-butyl}-azithromycin

Starting from Intermediate 16c (667.2 mg, 0.8 mmoL) and1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid (192.7 mg, 0.58 mmoL) using the similar procedure to that describedin Example 33 the title compound (460.3 mg) was obtained. MS (m/z) 1148(MH⁺).

Example 364″-O-{2-[4-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-piperazin-1-yl]-ethyl}-azithromycin11,12-cyclic carbonate

Intermediate 15 (114.4 mg, 0.14 mmoL) was dissolved in 0.9 mL ofmethanol. Three equivalents of Intermediate 17c (126.6 mg, 0.42 mmoL)were added as a 1 M solution in methanol (0.42 mL), followed by 0.43 mLof 1 M solution of acetic acid in methanol. The pH was checked andadjusted to about 6 with acetic acid, if necessary. NaCNBH₃ was added asa freshly prepared 0.3 M solution in methanol (0.19 mL), and the mixturewas stirred at room temperature for 2 h. The reaction was quenched witha few drops of water and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (1-5% MeOH/0.5-1%triethylamine/dichloromethane) to give 100.3 mg (75%) of the titlecompound as a yellow solid. MS (m/z) 1102 (MH⁺).

Example 374″-O-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylamino]-ethyl}-azithromycin11,12-cyclic carbonate

This method was adapted from the work of Debono et al. (J. Antibiot.1989, 42, 1253-1267). A solution of Intermediate 15 (955.9 mg, 1.17mmoL), Intermediate 1 (563.1 mg, 1.75 mmoL), and 22.5 mL of EtOAc washeated to 70° C. with stirring. Formic acid (58.9 mg, 1.28 mmoL) wasadded dropwise to the solution, and the temperature was lowered to 65°C. Stirring and heating was continued for 5 h. After cooling to roomtemperature, the reaction solution was washed twice with 25 mL portionsof saturated aqueous NaHCO₃ and then once with 20 mL of saturatedaqueous NaCl. The combined extracts were dried over anhydrous MgSO₄,filtered, and evaporated under reduced pressure to furnish crude productas a yellow foam. This material was taken up in 100 mL of hot Et₂O;insolubles were filtered and saved. The filtrate was treated with 30 mLof hot hexane, and again the resulting insoluble matter was filtered andsaved. The filtrate was concentrated to about 7.5 mL by boiling offexcess solvent. The resulting solution was allowed to cool to roomtemperature and then cooled to 5° C. for several hours. A colorlessprecipitate formed (630.6 mg). The filtrate was combined with theinsolubles that were saved, and the mixture was then chromatographed onsilica gel. Elution with 9:1 CH₂Cl₂-MeOH containing 1% NH₄OH afforded anadditional amount of the title product (420.3 mg, 80% overall yield). MS(m/z) 1122 (MH⁺).

Example 384″-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin11,12-cyclic carbonate

To a magnetically stirred solution of Intermediate 15 (2.17 g, 2.65mmoL) in 8 mL of methanol was added7-(2-amino-ethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4dihydro-quinoline-3-carboxylicacid (1.62 g, 5.3 mmol). After being stirred at room temperature for 30min, the solution was treated with 0.15 mL (2.65 mmoL) of HOAc andcooled to 0° C. In 2 mL of MeOH, 563.4 mg (2.66 mmoL) of NaBH(OAc)₃ wasthen added over a period of 10 min. Stirring and cooling was continuedfor 10 min. The reaction mixture was worked up and the crude product waschromatographed on silica gel to furnish 1.99 g (68%) of the titleproduct. MS (m/z) 1108 (MH⁺).

Example 394″-O-{2-[4-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-yl)-piperazin-1-yl]-ethyl}-azithromycin11,12-cyclic carbonate

Starting from Intermediate 14 (817 mg, 1.0 mmoL) and1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid (994.1 mg, 3.0 mmoL) using a similar procedure to that described inExample 36 the title compound (702.1 mg) was obtained. MS (m/z) 1132(MH⁺).

Example 404″-O-{2-[4-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-piperazin-1-yl]-ethyl}-azithromycin

To a solution of Example 36 (1.101 g, 1.0 mmoL) in a THF-water mixture(1:1, 10.0 mL), was added LiOH (192 mg, 4.6 mmoL) at room temperature,and the resulting reaction mixture was stirred at the same temperaturefor 12 hours. The solvent was removed under reduced pressure, and thesolid was azeotroped with toluene (5×5 mL) and finally dried undervacuum. The acid salt was dissolved in water and the resulting solutionwas made acidic by dropwise addition of aqueous HCl (2 M). Theprecipitate was filtered off to give 688.9 mg (64%) of the titlecompound as colourless solid. MS (m/z) 1076 (MH⁺).

Example 414″-O-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylamino]-ethyl}-azithromycin

Starting from Example 37 (504.9 mg, 0.45 mmoL) according to theprocedure of Example 40, the title compound (399.8 mg) was obtained. MS(m/z) 1096 (MH⁺).

Example 424″-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin

Starting from Example 38 (686.3 mg, 0.62 mmoL) according to theprocedure of Example 40, the title compound (671.1 mg) was obtained. MS(m/z) 1082 (MH⁺).

Biological Data

Using a standard broth dilution method in microtitre, compounds weretested for antibacterial activity. The compounds in the above examplesgave minimum inhibitory concentrations (MICs) less than 1 microgram permillilitre against erythromycin-sensitive and erythromycin-resistantstrains of Streptococcus pneumoniae and Streptococcus pyogenes.

In addition, the MIC (μg/ml) of test compounds against various organismswas determined including:

S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565, E.faecalis ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC23246.

Examples 1, 2, 5-7, 13, 15, 18-23, 25 and 27-32 have an MIC ≦1 μg/mLagainst S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes3565 and E. faecalis ATCC 29212.

Examples 1, 2, 4, 6, 13-16, 18-21, 23 and 27-32 have an MIC ≦4 μg/mLagainst H. influenzae ATCC 49247 and M. catarrhalis ATCC 23246.

Examples 1-4, 6, 7, 9-15 and 18-32 have an MIC ≦1 μg/mL againsterythromycin resistant strains of Streptococcus pneumoniae andStreptococcus pyogenes.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of formula (I)

wherein A is a bivalent radical selected from —C(O)—, —C(O)NH—,—NHC(O)—, —N(R⁷)—CH₂—, —CH₂—N(R⁷)—, —CH(NR⁸R⁹)— and —C(═NR¹⁰)—; R¹ is—O(CH₂)_(d)XR¹¹; R² is hydrogen or a hydroxyl protecting group; R³ ishydrogen, C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to 10membered fused bicyclic heteroaryl; R⁴ is hydroxy, C₃₋₆alkenyloxyoptionally substituted by 9 to 10 membered fused bicyclic heteroaryl, orC₁₋₆alkoxy optionally substituted by C₁₋₆alkoxy or —O(CH₂)_(e)NR⁷R¹², R⁵is hydroxy, or R⁴ and R⁵ taken together with the intervening atoms forma cyclic group having the following structure:

wherein Y is a bivalent radical selected from —CH₂—, —CH(CN)—, —O—,—N(R¹³)— and —CH(SR¹³)—; R⁶ is hydrogen or fluorine; R⁷ is hydrogen orC₁₋₆alkyl; R⁸ and R⁹ are each independently hydrogen, C₁₋₆alkyl,—C(═NR¹⁰)NR¹⁴R¹⁵ or —C(O)R¹⁴, or R⁸ and R⁹ together form═CH(CR¹⁴R¹⁵)_(f)aryl, ═CH(CR¹⁴R¹⁵)_(f)heterocyclyl, ═CR¹⁴R¹⁵ or═C(R¹⁴)C(O)OR¹⁴, wherein the alkyl, aryl and heterocyclyl groups areoptionally substituted by up to three groups independently selected fromR¹⁶; R¹⁰ is —OR¹⁷, C₁₋₆alkyl, —(CH₂)_(g)aryl, —(CH₂)_(g)heterocyclyl or—(CH₂)_(h)O(CH₂)_(i)OR⁷, wherein each R¹⁰ group is optionallysubstituted by up to three groups independently selected from R¹⁶; R¹¹is a heterocyclic group having the following structure:

R¹² is hydrogen or C₁₋₆alkyl; R¹³ is hydrogen or C₁₋₄alkyl optionallysubstituted by a group selected from optionally substituted phenyl,optionally substituted 5 or 6 membered heteroaryl and optionallysubstituted 9 to 10 membered fused bicyclic heteroaryl; R¹⁴ and R¹⁵ areeach independently hydrogen or C₁₋₆alkyl; R¹⁶ is halogen, cyano, nitro,trifluoromethyl, azido, —C(O)R²¹, —C(O)OR²¹, —OC(O)R²¹, —OC(O)OR²¹,—NR²²C(O)R²³, —C(O)NR²²R²³, —NR²²R²³, hydroxy, C₁₋₆alkyl,—S(O)_(k)C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(m)aryl or —(CH₂)_(m)heteroaryl,wherein the alkoxy group is optionally substituted by up to three groupsindependently selected from —NR¹⁴R¹⁵, halogen and —OR¹⁴, and the aryland heteroaryl groups are optionally substituted by up to five groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,azido, —C(O)R²⁴, —C(O)OR²⁴, —OC(O)OR²⁴, —NR²⁵C(O)R²⁶, —C(O)NR²⁵R²⁶,—NR²⁵R²⁶, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy; R¹⁷ is hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₆alkenyl or a 5 or 6 membered heterocyclic group,wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups areoptionally substituted by up to three substituents independentlyselected from optionally substituted 5 or 6 membered heterocyclic group,optionally substituted 5 or 6 membered heteroaryl, —OR²⁷, —S(O)_(n)R²⁷,—NR²⁷R²⁸, —CONR²⁷R²⁸, halogen and cyano; R¹⁸ is hydrogen, —C(O)OR²⁹,—C(O)NHR²⁹, —C(O)CH₂NO₂ or —C(O)CH₂SO₂R⁷; R¹⁹ is hydrogen, C₁₋₄alkyloptionally substituted by hydroxy or C₁₋₄alkoxy, C₃₋₇cycloalkyl, oroptionally substituted phenyl or benzyl; R²⁰ is halogen, C₁₋₄alkyl,C₁₋₄thioalkyl, C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl) or —N(C₁₋₄alkyl)₂; R²¹is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(p)aryl or —(CH₂)_(p)heteroaryl; R²² andR²³ are each independently hydrogen, —OR¹⁴, C₁₋₆alkyl, —(CH₂)_(q)aryl or—(CH₂)_(q)heterocyclyl; R²⁴ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(r)aryl or—(CH₂)_(r)heteroaryl; R²⁵ and R²⁶ are each independently hydrogen,—OR¹⁴, C₁₋₆alkyl, —(CH₂)_(s)aryl or —(CH₂)_(s)heterocyclyl; R²⁷ and R²⁸are each independently hydrogen, C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; R²⁹is hydrogen, C₁₋₆alkyl optionally substituted by up to three groupsindependently selected from halogen, cyano, C₁₋₄alkoxy optionallysubstituted by phenyl or C₁₋₄alkoxy, —C(O)C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—OC(O)C₁₋₆alkyl, —OC(O)OC₁₋₆alkyl, —C(O)NR³²R³³, —NR³²R³³ and phenyloptionally substituted by nitro or —C(O)OC₁₋₆alkyl,—(CH₂)_(w)C₃₋₇cycloalkyl, —(CH₂)_(w)heterocyclyl, —(CH₂)_(w)heteroaryl,—(CH₂)_(w)aryl, C₃₋₆alkenyl, or C₃₋₆alkynyl; R³⁰ is hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl, optionally substituted phenyl or benzyl, acetyl orbenzoyl; R³¹ is hydrogen or R²⁰, or R³¹ and R¹⁹ are linked to form thebivalent radical —O(CH₂)₂— or —(CH₂)_(t)—; R³² and R³³ are eachindependently hydrogen or C₁₋₆alkyl optionally substituted by phenyl or—C(O)OC₁₋₆alkyl, or R³² and R³³, together with the nitrogen atom towhich they are bound, form a 5 or 6 membered heterocyclic groupoptionally containing one additional heteroatom selected from oxygen,nitrogen and sulfur; X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a groupselected from:

U and B are independently a divalent radical selected from —N(R³⁰)—,—O—, —S(O)_(z)—, —N(R³⁰)C(O)—, —C(O)N(R³⁰)— and —N[C(O)R³⁰]—; W is—C(R³¹)— or a nitrogen atom; d is an integer from 2 to 6; e is aninteger from,2 to 4; f, g, h, m, p, q, r, s and w are each independentlyintegers from 0 to 4; i is an integer from 1 to 6; j, k, n and z areeach independently integers from 0 to 2; t is 2 or 3; v is an integerfrom 1 to 8; or a pharmaceutically acceptable derivative thereof.
 2. Acompound according to claim 1 wherein A is —C(O)— or —N(R⁷)—CH₂—.
 3. Acompound according to claim 1 wherein X is —U(CH₂)_(v)B— or —U(CH₂)_(v).4. A compound according to claim 1 wherein d is 2 or
 3. 5. A compoundaccording to claim 1 wherein R¹¹ is a heterocyclic group of thefollowing formula:

wherein the heterocyclic is linked in the 6 or 7 position and j, R¹⁸,R¹⁹ and R²⁰ are as defined in claim 1; a heterocyclic group of thefollowing formula:

wherein the heterocylic is linked in the (ii) or (iii) position, W is—C(R³¹)— and R³¹ and R¹⁹ are linked to form the bivalent radical—(CH₂)_(t)— as defined in claim 1, and j, R¹⁸, R¹⁹ and R²⁰ are asdefined in claim 1; or a heterocyclic group of the following formula:

wherein the heterocyclic is linked in the 7 or 8 position and j, R¹⁸,R¹⁹ and R²⁰ are as defined in claim
 1. 6. A compound according to claim1 as defined in any one of Examples 1 to 42, or a pharmaceuticallyacceptable derivative thereof.
 7. A compound selected from:4″-O-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-erythromycinA 11,12-carbonate;4″-O-(3-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate;4″-O-{3-[2-(2-carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycinA 11,12-carbonate;4″-O-(3-{[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate;4″-O-(3-{[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycinA 11,12-carbonate;4″-O-{2-[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-ethyl}-6-O-methyl-erythromycinA;4″-O-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate;4″-O-{3-[[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycinA 11,12-carbamate;4″-O-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylcarbamoyl]-propyl}-azithromycin;4″-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin11,12-cyclic carbonate;4″-O-{2-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylamino]-ethyl}-azithromycin;and4″-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin;or a pharmaceutically acceptable derivative thereof.
 8. A process forthe preparation of a compound as claimed in claim 1 which comprises: a)reacting a compound of formula (II)

 with a suitable amine (IIIa) or (IIIb), wherein B^(a) and R^(11a) are Band R¹¹ as defined in claim 1 or groups convertible to B and R¹¹; b)reacting a compound of formula (V)

with a compound of formula X^(a)R^(11a) (IV), wherein R^(11a) is R¹¹ asdefined in claim 1 or a group convertible to R¹¹ and X^(a) is—U(CH₂)_(v)— or —U(CH₂)_(v)B—, or a group convertible to —U(CH₂)_(v)— or—U(CH₂)_(v)B—, in which U is a group selected from —N(R³⁰)— and —S—, andL is suitable leaving group, to produce a compound of formula (I)wherein U is a group selected from —N(R³⁰)— and —S—; a) converting onecompound of formula (I) into another compound of formula (I); d) where Uis —O—, reacting a compound of formula (VII)

 with a suitable compound of formula X^(a)R^(11a) in the presence of acatalyst; or e) where U is —C(O)N(R³⁰)—, reacting a compound of formula(VIII)

 with a suitable amine compound, and thereafter, if required, subjectingthe resulting compound to one or more of the following operations: i)removal of the protecting group R², ii) conversion of X^(a)R^(11a) toXR¹¹, iii) conversion of B^(a)R^(11a) to R¹¹, iv) conversion of R^(11a)to R¹¹, and v) conversion of the resultant compound of formula (I) intoa pharmaceutically acceptable derivative thereof.
 9. A compound asclaimed in claim 1 for use in therapy. 10-11. (canceled)
 12. A methodfor the treatment of the human or non-human animal body to combatmicrobial infection comprising administration to a body in need of suchtreatment of an effective amount of a compound as claimed in claim 1.13. A pharmaceutical composition comprising at least one compound asclaimed in claim 1 in association with a pharmaceutically acceptableexcipient, diluent and/or carrier.
 14. A compound of formula (IA)

wherein A is a bivalent radical selected from —C(O)—, —C(O)NH—,—NHC(O)—, —N(R⁷)—CH₂—, —CH₂—N(R⁷)—, —CH(NR⁸R⁹)— and —C(═NR¹⁰)—; R¹ is—O(CH₂)_(d)XR¹¹; R² is hydrogen or a hydroxyl protecting group; R³ ishydrogen, C₁₋₄alkyl, or C₃₋₆alkenyl optionally substituted by 9 to 10membered fused bicyclic heteroaryl; R⁴ is hydroxy, C₃₋₆alkenyloxyoptionally substituted by 9 to 10 membered fused bicyclic heteroaryl, orC₁₋₆alkoxy optionally substituted by C₁₋₆alkoxy or —O(CH₂)_(e)NR⁷R¹², R⁵is hydroxy, or R⁴ and R⁵ taken together with the intervening atoms forma cyclic group having the following structure:

wherein Y is a bivalent radical selected from —CH₂—, —CH(CN)—, —O—,—N(R¹³)— and —CH(SR¹³)—; R⁶ is hydrogen or fluorine; R⁷ is hydrogen orC₁₋₆alkyl; R⁸ and R⁹ are each independently hydrogen, C₁₋₆alkyl,—C(═NR¹⁰)NR¹⁴R¹⁵ or —C(O)R¹⁴, or R⁸ and R⁹ together form═CH(CR¹⁴R¹⁵)_(f)aryl, ═CH(CR¹⁴R¹⁵)_(f)heterocyclyl, ═CR¹⁴R¹⁵ or═C(R¹⁴)C(O)OR¹⁴, wherein the alkyl, aryl and heterocyclyl groups areoptionally substituted by up to three groups independently selected fromR¹⁶; R¹⁰ is —OR¹⁷, C₁₋₆alkyl, —(CH₂)_(g)aryl, —(CH₂)_(g)heterocyclyl or—(CH₂)_(h)O(CH₂)_(i)OR⁷, wherein each R¹⁰ group is optionallysubstituted by up to three groups independently selected from R¹⁶; R¹¹is a heterocyclic group having the following structure:

R¹² is hydrogen or C₁₋₆alkyl; R¹³ is hydrogen or C₁₋₄alkyl substitutedby a group selected from optionally substituted phenyl, optionallysubstituted 5 or 6 membered heteroaryl and optionally substituted 9 to10 membered fused bicyclic heteroaryl; R¹⁴ and R¹⁵ are eachindependently hydrogen or C₁₋₆alkyl; R¹⁶ is halogen, cyano, nitro,trifluoromethyl, azido, —C(O)R²¹, —C(O)OR²¹, —OC(O)R²¹, —OC(O)OR²¹,—NR²²C(O)R²³, —C(O)NR²²R²³, —NR²²R²³, hydroxy, C₁₋₆alkyl,—S(O)_(k)C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(m)aryl or —(CH₂)_(m)heteroaryl,wherein the alkoxy group is optionally substituted by up to three groupsindependently selected from —NR¹⁴R¹⁵, halogen and —OR¹⁴, and the aryland heteroaryl groups are optionally substituted by up to five groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,azido, —C(O)R²⁴, —C(O)OR²⁴, —OC(O)OR²⁴, —NR²⁵C(O)R²⁶, —C(O)NR²⁵R²⁶,—NR²⁵R²⁶, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy; R¹⁷ is hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₆alkenyl or a 5 or 6 membered heterocyclic group,wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups areoptionally substituted by up to three substituents independentlyselected from optionally substituted 5 or 6 membered heterocyclic group,optionally substituted 5 or 6 membered heteroaryl, —OR²⁷, —S(O)_(n)R²⁷,—NR²⁷R²⁸, —CONR²⁷R²⁸, halogen and cyano; R¹⁸ is hydrogen, —C(O)OR²⁹,—C(O)NHR²⁹ or —C(O)CH₂NO₂; R¹⁹ is hydrogen, C₁₋₄alkyl optionallysubstituted by hydroxy or C₁₋₄alkoxy, C₃₋₇cycloalkyl, or optionallysubstituted phenyl or benzyl; R²⁰ is halogen, C₁₋₄alkyl, C₁₋₄thioalkyl,C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl) or —N(C₁₋₄alkyl)₂; R²¹ is hydrogen,C₁₋₁₀alkyl, —(CH₂)_(p)aryl or —(CH₂)_(p)heteroaryl; R²² and R²³ are eachindependently hydrogen, —OR¹⁴, C₁₋₆alkyl, —(CH₂)_(q)aryl or—(CH₂)_(q)heterocyclyl; R²⁴ is hydrogen, C₁₋₁₀alkyl, —(CH₂)_(r)aryl or—(CH₂)_(r)heteroaryl; R²⁵ and R²⁶ are each independently hydrogen,—OR¹⁴, C₁₋₆alkyl, —(CH₂)_(s)aryl or —(CH₂)_(s)heterocyclyl; R²⁷ and R²⁸are each independently hydrogen, C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; R²⁹is hydrogen or C₁₋₆alkyl optionally substituted by up to three groupsindependently selected from halogen, C₁₋₄alkoxy, —OC(O)C₁₋₆alkyl and—OC(O)OC₁₋₆alkyl; R³⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, optionallysubstituted phenyl or benzyl, acetyl or benzoyl; R³¹ is hydrogen or R²⁰,or R³¹ and R¹⁹ are linked to form the bivalent radical —O(CH₂)₂— or—(CH₂)_(t)—; X is —U(CH₂)_(v)B—, —U(CH₂)_(v)— or a group selected from:

U and B are independently a divalent radical selected from —N(R³⁰)—,—O—, —S(O)_(z)—, —N(R³⁰)C(O)—, —C(O)N(R³⁰)— and —N[C(O)R³⁰]—; W is—C(R³¹)— or a nitrogen atom; d is an integer from 2 to 6; e is aninteger from 2 to 4; f, g, h, m, p, q, r and s are each independentlyintegers from 0 to 4; i is an integer from 1 to 6; j, k, n and z areeach independently integers from 0 to 2; t is 2 or 3; v is an integerfrom 2 to 8; or a pharmaceutically acceptable derivative thereof.